Pharmaceutically active disubstituted pyridine derivatives

ABSTRACT

The present invention relates to disubstituted pyridine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of infectious diseases, including opportunistic diseases, immunological diseases, autoimmune diseases, cardiovascular diseases, cell proliferative diseases, inflammation, erectile dysfunction and stroke, and pharmaceutical compositions containing at least one of said disubstituted pyridine derivatives and/or pharmaceutically acceptable salts thereof. Furthermore, the present invention relates to the use of said disubstituted pyridine derivatives as inhibitors for a protein kinase.

The present invention relates to disubstituted pyridine derivativesand/or pharmaceutically acceptable salts thereof, the use of thesederivatives as pharmaceutically active agents, especially for theprophylaxis and/or treatment of cell proliferative diseases,inflammatory and immunological diseases, cardiovascular diseases andinfectious diseases. Furthermore, the present invention is directedtowards pharmaceutical composition containing at least one of thedisubstituted pyridine derivatives and/or pharmaceutically acceptablesalts thereof.

Cyclin-dependent kinase (CDK) family members that trigger passagethrough the cell cycle are being considered as attractive therapeutictargets, especially for cancer. CDK family members that control otherprocesses such as transcription and RNA processing have caught lessattention so far, although experimental evidence for their involvementin different pathological processes is emerging. As a general regulatorof transcription, CDK9 is a therapeutic target for treatment of diseaseslike inflammation, virus replication such as HIV, EBV, and HCV, cancerand cardiac hypertrophy.

CDK9 regulates transcription by phosphorylation of RNA polymerase II aswell as additional regulatory factors, thereby enabling productiveelongation of transcription. Certain subgroups of genes, especiallygenes encoding RNAs or proteins with fast turnover like immediate earlygenes of the inflammatory response, NF-kappaB activated genes (Brasier2008, Cell Cycle 7:17, 2661-2666, Hargreaves et al. (2009) Cell 138,129-145); and antiapoptotic genes such as MCL-1 and Bcl-2 family membersappear to be especially sensitive to CDK9 inhibition.

In addition, it has been reported that hypertrophic growth ofcardiomyocytes is related to CDK9 activation. Furthermore, viruses likethe human immune deficiency virus recruit CDK9 actively to nascent RNAtranscripts, facilitating their replicating. The dependency of theexpression of antiapoptotic genes on CDK9 activity makes it anattractive therapeutic target for various forms of leukaemia such aschronic lymphocytic leukaemia (CLL), acute myelogenous leukaemia (AML)and acute lymphoblastic leukaemia, and solid tumours like prostate,lung, colon, breast and pancreas cancer. In addition, CDK9 inhibitorshave been active in models of stroke (Osuga 2000, PNAS 97 (18):10254-10259).

For reviews, see Wang, 2009 (Trends in Pharmacological Sciences 29:6,302-313), and Kohoutek, 2009 (Cell Division 2009, 4:19).

BACKGROUND OF THE INVENTION

The present literature discloses several attempts to provide compoundsfor the use of modulating the activity of protein kinases. The inventionof US 2011/028492 A1, filed on Jul. 26, 2010, by Barsanti et al.,provides bipyridyl compounds and derivatives as such and for use aspharmaceutical compounds in medicine. The disclosed structures comprisepyridyl-, pyrazinyl- and triazinyl-pyridines:

wherein A₁-A₃ represent independently of each other: N or C—R;

On the other hand the invention of WO 2008/079933 A2, filed on Dec. 20,2007, by NOVARTIS AG, also provides bipyridyl compounds and derivativesas such and for use as pharmaceutical compounds in medicine. Thedisclosed structures comprise pyridyl-, pyrazinyl- andtriazinyl-pyridines:

wherein A¹-A⁴ represent independently of each other: N or C—R;

Due to the fact that the focus of US 2011/028492 A1 and WO 2008/079933A2 is directed to pyridyl-pyridines, pyrazinyl-pyridines andtriazinyl-pyridines both state of the art documents relate tostructurally different compounds containing nitrogen heterocyclic groupsthan disclosed in the present invention so that the compounds disclosedin US 2011/028492 A1 and WO 2008/079933 A2 do not challenge novelty orinventiveness of the compounds disclosed herein.

It is object of the present invention to provide compounds and/orpharmaceutically acceptable salts thereof which can be used aspharmaceutically active agents, especially for prophylaxis and/ortreatment of cell proliferative diseases, inflammatory diseases,immunological diseases, cardiovascular diseases and infectious diseases,as well as compositions comprising at least one of those compoundsand/or pharmaceutically acceptable salts thereof as pharmaceuticallyactive ingredients.

This object is solved by the compounds and/or their pharmaceuticallyacceptable salts according to independent claim 1, the compounds of thepresent invention for use as pharmaceutically active agents, the use ofthe compounds of the present invention for the preparation of apharmaceutical composition for the prophylaxis and/or treatment ofinfectious diseases, including opportunistic diseases, immunologicaldiseases, autoimmune diseases, cardiovascular diseases, cellproliferative diseases, inflammation, erectile dysfunction and strokeaccording to independent claim 6, the use of compounds according to thepresent invention as inhibitors for the protein kinase CDK9.

Further advantageous features, aspects and details of the invention areevident from the dependent claims, the description, the examples and thedrawings.

The novel disubstituted pyridine compounds according to the presentinvention are defined by the general formula (I)

whereinR¹ is

L is a bond or —CR⁵R⁶—, —CR⁵R⁶—CR⁷R⁸—, —CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰,—CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰—CR¹¹R¹²;R⁵—R¹² represent independently of each other —H, —CH₃, —C₂H₅, —C₃H₇, —F,—Cl, —Br, —I;R³ is selected from —H, —NO₂, —NH₂, —CN, —F, —Cl, —Br, —I, —CH₃, —C₂H₅,—C₃H₇, —CH(CH₃)₂, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —O—CH₃,—O—C₂H₅, —O—C₃H₇, —O—CH(CH₃)₂, —O—C₄H₉, —O—CH₂—CH(CH₃)₂,—O—CH(CH₃)—C₂H₅, —O—C(CH₃)₃, —CR¹³R¹⁴R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶R²¹,—O—CR¹³R¹⁴R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰R²¹, —O—CR¹³R¹⁴—CR¹⁵R¹⁶R²¹,—O—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸R²¹, —SO₂R²², —CONR²³R²⁴, —NR²⁵COR²²,—O—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰R²¹, —NR²⁵SO₂NR²³R²⁴, —NR²⁵SO₂R²²,—NR²⁵CONR²³R²⁴, —SO₂NR²³R²⁴, —SO(NR²⁶)R²², —NR²³R²⁴;R¹³—R²¹ and R²⁹—R³² represent independently of each other —H, —CH₃,—C₂H₅, —C₃H₇, —C₄H₉, —F, —Cl, —Br, —I;R²⁶ is —H, —CH₃, —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉, —CH₂—CH(CH₃)₂,—CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁, —CH(CH₃)—C₃H₇, —CH₂—CH(CH₃)—C₂H₅,—CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅, —CH₂—C(CH₃)₃, —CH(C₂H₅)₂,—C₂H₄—CH(CH₃)₂, —C₆H₁₃, —C₃H₆—CH(CH₃)₂, —C₂H₄—CH(CH₃)—C₂H₅,—CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇, —CH(CH₃)—CH₂—CH(CH₃)₂,—CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂, —CH₂—C(CH₃)₂—C₂H₅,—C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃, —CH(CH₃)—C(CH₃)₃,—CR¹³R¹⁴R²¹, —COR²⁸, —CR¹³R¹⁴—CR¹⁵R¹⁶R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰—CR³¹R³²R²¹, —COOR²⁸, —R²⁷,R²², and R²⁸ are independently selected from —R^(27′), —CR¹³R¹⁴R²¹,—CH₃, —C₂H₅, —C₃H₇, —CR¹³R¹⁴—CR¹⁵R¹⁶R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰—CR³¹R³²R²¹, —CH₂Ph; —CH₂Ph thephenyl group of which may further be substituted by one, two, three,four or five substituents selected from the group consisting of —CH₃,—C₂H₅, —C₃H₇, —F, —Cl, —Br and —I;R²⁷, R^(27′) and R^(27″) are independently selected from

these C₃-C₁₀-cycloalkyl groups may further be substituted by one, two,three, four, five or more substituents selected from the groupconsisting of —F, —Cl, —Br and —I;R²³, R²⁴, R⁷⁷ and R⁷⁸ are independently selected from —H, —CH₃,—CR¹³R¹⁴R²¹, —C₂H₅, —C₃H₇, —CR¹³R¹⁴—CR¹⁵R¹⁶R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰—CR³¹R³²R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—O—R³³, —CR¹³R¹⁴—CR¹⁵R¹⁶—NR³³R³⁴,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—NR³³R³⁴,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—NR³³R³⁴,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—O—R³³,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰—NR³³R³⁴, -Ph, —CH₂Ph, phenylgroup which may further be substituted by one, two, three, four or fivesubstituents selected from the group consisting of —CH₃, —C₂H₅, —C₃H₇,—F, —Cl, —Br and —I;—CH₂Ph the phenyl group of which may further be substituted by one, two,three, four or five substituents selected from the group consisting of—CH₃, —C₂H₅, —C₃H₇, —F, —Cl, —Br and —I; orboth residues R²³ and R²⁴ together form with the nitrogen atom to whichthey are attached a azetidine, pyrrolidine, piperidine, piperazine,azepane, or morpholine ring;R³³ and R³⁴ represent independently of each other —H, —CH₃, —C₂H₅,—C₃H₇, —C₄H₉, —CH₂Ph, —COOC(CH₃)₃, —COOCH₃, —COOCH₂CH₃, —COOCH₂CH₂CH₃,—COOCH(CH₃)₂, —COOCH₂Ph, —COCH₃;and R²⁵ is selected from —H, —CH₃, —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅ or —C(CH₃)₃;R⁴ is selected from —H, —NO₂, —CN, —F, —Cl, —Br, —I, —CR³⁵R³⁶R³⁷,—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³R³⁷, —O—CR³⁵R³⁶—CR³⁸R³⁹R³⁷,—O—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹R³⁷, —CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹R³⁷,—O—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³R³⁷, —CR³⁵R³⁶—CR³⁸R³⁹R³⁷,—O—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³—CR⁴⁴R⁴⁵R³⁷, —O—CR³⁵R³⁶R³⁷,—O—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³—CR⁴⁴R⁴⁵—CR⁴⁶R⁴⁷R³⁷,—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³—CR⁴⁴R⁴⁵R³⁷,—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³—CR⁴⁴R⁴⁵—CR⁴⁶R⁴⁷R³⁷, —OCH₂Ph, —R^(27″),—O—R^(27″),R³⁵—R⁴⁷ and R⁶²—R⁷⁴ represent independently of each other —H,—CR⁴⁸R⁴⁹R⁵⁰, —CR⁴⁸R⁴⁹—CR⁵¹R⁵²R⁵⁰, —CR⁴⁸R⁴⁹—CR⁵¹R⁵²—CR⁵³R⁵⁴R⁵⁰,—CR⁴⁸R⁴⁹—CR⁵¹R⁵²—CR⁵³R⁵⁴—CR⁵⁵R⁵⁶R⁵⁰, —F, —Cl, —Br, —I;R⁴⁸—R⁵⁶ represent independently of each other —H, —F, —Cl, —Br, —I;R⁴ together with R²² or R²³ or R²⁴ or R²⁵ may form a group —CH₂CH₂— or—CH₂CH₂CH₂— if R⁴ is attached ortho to -L-R³;R² is

R⁵⁷ is selected from —H, —OH, —NO₂, —CN, —F, —Cl, —Br, —I, —NR⁶⁰R⁶¹,-D-R⁶⁴, -D-NR⁶⁰R⁶¹, —O-D-R⁶⁴, —CHO, —CH₂OH, —CO—R⁶⁰, —CH₂OR⁶⁰;D, D′ and D″ represent independently of each other —CR⁶²R⁶³—,—CR⁶²R⁶³—CR⁶⁵R⁶⁶—, —CR⁶²R⁶³—CR⁶⁵R⁶⁶—CR⁶⁷R⁶⁸—,CR⁶²R⁶³—CR⁶⁵R⁶⁶—CR⁶⁷R⁶⁸—CR⁶⁹R⁷⁰—;R⁶⁰, R⁶¹, R⁷⁵ and R⁷⁶ represent independently of each other —H, —CH₃,—C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃;-(cyclo-C₃H₅);x is 0, 1, 2 or 3;B is a bond, -D′-, -E-;E and E′ represent independently of each other—CR⁶²R⁶³—CR⁶⁵R⁶⁶—CR⁶⁷R⁶⁸—CR⁶⁹R⁷⁰—CR⁷¹R⁷²—,—CR⁶²R⁶³—CR⁶⁵R⁶⁶—CR⁶⁷R⁶⁸—CR⁶⁹R⁷⁰—CR⁷¹R⁷²—CR⁷³R⁷⁴—;Y is a bond, —O—, —S—, —SO—, —SO₂—, —SO₂NH—, —NHSO₂—, —CO—, —COO—,—OOC—, —CONH—, —NHCO—, —NH—, —N(CH₃)—, —NH—CO—NH—, —O—CO—NH—, —NH—CO—O—;R⁵⁸ is selected from a bond, -D″-, -E′-;R⁵⁹ is selected from(i) —H, —OH, —OCH₃, —OC₂H₅, —OC₃H₇, —O-cyclo-C₃H₅, —OCH(CH₃)₂,—OC(CH₃)₃, —OC₄H₉, -Ph, —OPh, —OCH₂-Ph, —OCPh₃, —SH, —SCH₃, —SC₂H₅,—SC₃H₇, —S-cyclo-C₃H₅, —SCH(CH₃)₂, —SC(CH₃)₃, —SC₄H₉, —NO₂, —F, —Cl,—Br, —I, —P(O)(OH)₂, —P(O)(OCH₃)₂, —P(O)(OC₂H₅)₂, —P(O)(OCH(CH₃)₂)₂,—Si(CH₃)₂(C(CH₃)₃), —Si(C₂H₅)₃, —Si(CH₃)₃, —CN, —CHO, —COCH₃, —COC₂H₅,—COC₃H₇, —CO-cyclo-C₃H₅, —COCH(CH₃)₂, —COC(CH₃)₃, —COC₄H₉, —COOH,—COOCH₃, —COOC₂H₅, —COOC₃H₇, —COOC₄H₉, —COO-cyclo-C₃H₅, —COOCH(CH₃)₂,—COOC(CH₃)₃, —OOC—CH₃, —OOC—C₂H₅, —OOC—C₃H₇, —OOC—C₄H₉, —OOC-cyclo-C₃H₅,—OOC—CH(CH₃)₂, —OOC—C(CH₃)₃, —CONR⁷⁵R⁷⁶, —NHCOCH₃, —NHCOC₂H₅, —NHCOC₃H₇,—NHCO-cyclo-C₃H₅, —NHCO—CH(CH₃)₂, —NHCOC₄H₉, —NHCO—C(CH₃)₃, —NHCO—OCH₃,—NHCO—OC₂H₅, —NHCO—OC₃H₇, —NHCO—O-cyclo-C₃H₅, —NHCO—OC₄H₉,—NHCO—OCH(CH₃)₂, —NHCO—OC(CH₃)₃, —NHCO—OCH₂Ph, —NR⁷⁷R⁷⁸, —SOCH₃,—SOC₂H₅, —SOC₃H₇, —SO-cyclo-C₃H₅, —SOCH(CH₃)₂, —SOC(CH₃)₃, —SO₂CH₃,—SO₂C₂H₅, —SO₂C₃H₇, —SO₂-cyclo-C₃H₅, —SO₂CH(CH₃)₂, —SO₂C₄H₉,—SO₂C(CH₃)₃, —SO₃H, —SO₂NR⁷⁵R⁷⁶, —OCF₃, —OC₂F₅, —O—COOCH₃, —O—COOC₂H₅,—O—COOC₃H₇, —O—COO-cyclo-C₃H₅, —O—COOC₄H₉, —O—COOCH(CH₃)₂, —O—COOCH₂Ph,—O—COOC(CH₃)₃, —NH—CO—NH₂, —NH—CO—NHCH₃, —NH—CO—NHC₂H₅, —NH—CO—NHC₃H₇,—NH—CO—NHC₄H₉, —NH—CO—NH-cyclo-C₃H₅, —NH—CO—NH[CH(CH₃)₂],—NH—CO—NH[C(CH₃)₃], —NH—CO—N(CH₃)₂, —NH—CO—N(C₂H₅)₂, —NH—CO—N(C₃H₇)₂,—NH—CO—N(C₄H₉)₂, —NH—CO—N(cyclo-C₃H₅)₂, —NH—CO—N[CH(CH₃)₂]₂,—NH—CO—N[C(CH₃)₃]₂, —NH—C(═NH)—NH₂, —NH—C(═NH)—NHCH₃, —NH—C(═NH)—NHC₂H₅,—NH—C(═NH)—NHC₃H₇, —NH—C(═NH)—NHC₄H₉, —NH—C(═NH)—NH-cyclo-C₃H₅,—NH—C(═NH)—NH[CH(CH₃)₂], —NH—C(═NH)—NH[C(CH₃)₃], —NH—C(═NH)—N(CH₃)₂,—NH—C(═NH)—N(C₂H₅)₂, —NH—C(═NH)—N(C₃H₇)₂, —NH—C(═NH)—N(cyclo-C₃H₅)₂,—NH—C(═NH)—N(C₄H₉)₂, —NH—C(═NH)—N[CH(CH₃)₂]₂, —NH—C(═NH)—N[C(CH₃)₃]₂,—O—CO—NH₂, —O—CO—NHCH₃, —O—CO—NHC₂H₅, —O—CO—NHC₃H₇, —O—CO—NHC₄H₉,—O—CO—NH-cyclo-C₃H₅, —O—CO—NH[CH(CH₃)₂], —O—CO—NH[C(CH₃)₃],—O—CO—N(CH₃)₂, —O—CO—N(C₂H₅)₂, —O—CO—N(C₃H₇)₂, —O—CO—N(C₄H₉)₂,—O—CO—N(cyclo-C₃H₅)₂, —O—CO—N[CH(CH₃)₂]₂, —O—CO—N[C(CH₃)₃]₂,(ii) an aromatic or heteroaromatic mono- or bicyclic ring selected from2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazolyl, 3-oxazolyl,4-oxazolyl, 2-thiazolyl, 3-thiazolyl, 4-thiazolyl, 1-pyrazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 1-imidazolyl, 2-imidazolyl,4-imidazolyl, 5-imidazolyl, phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,2-pyrazinyl, 3-pyridazinyl, 4-pyridazinyl, 1,3,5-triazin-2-yl,

which optionally may be substituted by one or two substituents selectedfrom —F, —Cl, —Br, —I, —OCH₃, —CH₃, —NO₂, —CN, —CF₃;(iii) a saturated ring selected from

R⁷⁹ represents —H, —CH₃, —CH₂Ph, —COOC(CH₃)₃, —COOCH₃, —COOCH₂CH₃,—COOCH₂CH₂CH₃, —COOCH(CH₃)₂, —COOCH₂Ph, —COCH₃;the group —B—Y—R⁵⁸—R⁵⁹ together with one substituent R⁵⁷ may form agroup —OCH₂O—, if R⁵⁷ is attached in position ortho to —B—Y—R⁵⁸—R⁵⁹;with the proviso that R⁵⁹ is not —H, if B, Y and R⁵⁸ are bonds;and enantiomers, stereoisomeric forms, mixtures of enantiomers,diastereomers, mixtures of diastereomers, prodrugs, hydrates, solvates,acid salt forms, tautomers, and racemates of the above mentionedcompounds and pharmaceutically acceptable salts thereof.

The expression prodrug is defined as a substance, which is applied in aninactive or significantly less active form. Once applied andincorporated, the prodrug is metabolized in the body in vivo into theactive compound.

The expression tautomer is defined as an organic compound that isinterconvertible by a chemical reaction called tautomerization.Tautomerization can be catalyzed preferably by bases or acids or othersuitable compounds.

Preferred are compounds having the general formula (I):

whereinR¹ represents

in whichL is a bond, —CH₂—, —CH₂CH₂—, or —CF₂—, particularly preferred —CH₂—;R³ is —SO₂NH₂, —SO₂NH(CH₃), —SO₂N(CH₃)₂, —SO₂NH(CH₂CH₂OCH₃), —NHSO₂CH₃,—NHSO₂CH₂CH₃, —NHSO₂CH₂CH₃, —NHSO₂CF₃, —SO₂CH₃, —NHSO₂NH₂, —SO(NH)CH₃,—NH₂, particularly preferred —SO₂NH₂;R⁴ is —H, —CH₃, —F, —Cl, or —CF₃, particularly preferred —H;R² is

in which the group —B—Y—R⁵⁸—R⁵⁹ is —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,—OCH₂CH₂CH₂CH₃, —OCH(CH₃)₂, —OPh, —OCH₂Ph, —OCH₂(4-pyridyl),particularly preferred —OCH₃;R⁵⁷ is —H, —F, or —Cl;x is 0, 1, or 2.

In a further aspect of the present invention, the novel compoundsaccording to the general formula (I) represent chiral compounds. Thenovel compounds according to the general formula (I) represent aracemate, or a S or a R enantiomer or a mixture of isomers.

Preferably R³ represents —NO₂, —NH₂, —CN, —F, —Cl, —Br, —I, —SO₂R²²,—CONR²³R²⁴, —NR²⁵COR²², —NR²⁵SO₂NR²³R²⁴, —NR²⁵SO₂R²², —NR²⁵CONR²³R²⁴,—SO₂NR²³R²⁴, —SO(NR²⁶)R²², or —NR²³R²⁴. More preferably R³ represents—NO₂, —NH₂, —SO₂R²², —CONR²³R²⁴, —NR²⁵COR²², —NR²⁵SO₂NR²³R²⁴,—NR²⁵SO₂R²², —NR²⁵CONR²³R²⁴, —SO₂NR²³R²⁴, —SO(NR²⁶)R²², or —NR²³R²⁴.Most preferably R³ represents —NO₂, —NH₂, —SO₂R²², —NR²⁵COR²²,—NR²⁵SO₂R²², or —SO₂NR²³R²⁴.

It is also preferred if L represents a bond, —CH₂—, —CH₂CH₂—, or —CF₂—.More preferably L represents a bond, —CH₂—, or —CH₂CH₂—.

The residue-L-R³ represents preferably —NO₂, —NH₂, —SO₂R²², —CONR²³R²⁴,—NR²⁵COR²², —NR²⁵SO₂NR²³R²⁴, —NR²⁵SO₂R²², —NR²⁵CONR²³R²⁴, —SO₂NR²³R²⁴,—SO(NR²⁶)R²², —NR²³R²⁴, —CH₂—NO₂, —CH₂—NH₂, —CH₂—SO₂R²², —CH₂—CONR²³R²⁴,—CH₂—NR²⁵COR²², —CH₂—NR²⁵SO₂NR²³R²⁴, —CH₂—NR²⁵SO₂R²²,—CH₂—NR²⁵CONR²³R²⁴, —CH₂—SO₂NR²³R²⁴, —CH₂—SO(NR²⁶)R²², —CH₂—NR²³R²⁴,—CH₂CH₂—NO₂, —CH₂CH₂—NH₂, —CH₂CH₂—SO₂R²², —CH₂CH₂—CONR²³R²⁴,—CH₂CH₂—NR²⁵COR²², —CH₂CH₂—NR²⁵SO₂NR²³R²⁴, —CH₂CH₂—NR²⁵SO₂R²²,—CH₂CH₂—NR²⁵CONR²³R²⁴, —CH₂CH₂—SO₂NR²³R²⁴, —CH₂CH₂—SO(NR²⁶)R²², or—CH₂CH₂—NR²³R²⁴. More preferably the residue-L-R³ represents preferably—NO₂, —NH₂, —SO₂R²², —NR²⁵COR²², —NR²⁵SO₂R²², —SO₂NR²³R²⁴, —CH₂—NO₂,—CH₂—NH₂, —CH₂—SO₂R²², —CH₂—NR²⁵COR²², —CH₂—NR²⁵SO₂R²², —CH₂—SO₂NR²³R²⁴,—CH₂CH₂—NO₂, —CH₂CH₂—NH₂, —CH₂CH₂—SO₂R²², —CH₂CH₂—NR²⁵COR²²,—CH₂CH₂—NR²⁵SO₂R²², or —CH₂CH₂—SO₂NR²³R²⁴.

The following general formula are also especially preferred:

wherein -L-R³, —R⁴, —B—Y—R⁵⁸—R⁵⁹ and —R⁵⁷ have the meanings as definedherein.

Moreover in all general formulas disclosed herein the residue-L-R³represents more preferably —NO₂, —NH₂, —SO₂R²², —CONHR²³, —CON(R²³)₂,—NHCOR²², —NHSO₂NHR²³, —NHSO₂N(R²³)₂, —NHSO₂R²², —NHCONHR²³,—NHCON(R²³)₂, —SO₂NHR²³, —SO₂N(R²³)₂, —SO(NH)R²², —NHR²³, —N(R²³)₂,—CH₂—NO₂, —CH₂—NH₂, —CH₂—SO₂R²², —CH₂—CONHR²³, —CH₂—CON(R²³)₂,—CH₂—NHCOR²², —CH₂—NHSO₂NHR²³, —CH₂—NHSO₂N(R²³)₂, —CH₂—NHSO₂R²²,—CH₂—NHCONHR²³, —CH₂—NHCON(R²³)₂, —CH₂—SO₂NHR²³, —CH₂—SO₂N(R²³)₂,—CH₂—SO(NH)R²², —CH₂—NHR²³, —CH₂—N(R²³)₂, —CH₂CH₂—NO₂, —CH₂CH₂—NH₂,—CH₂—CH₂—SO₂R²², —CH₂—CH₂—NHSO₂NHR²³, —CH₂—CH₂—NHSO₂N(R²³)₂,—CH₂—CH₂—NHSO₂R²², —CH₂—CH₂—NHCONHR²³, —CH₂—CH₂—NHCON(R²³)₂,—CH₂—CH₂—SO₂NHR²³, —CH₂—CH₂—SO₂N(R²³)₂, —CH₂—CH₂—SO(NH)R²²,—CH₂—CH₂—NHR²³, —CH₂—CH₂—N(R²³)₂, —CH₂—CH₂—CONHR²³, —CH₂—CH₂—CON(R²³)₂,or —CH₂—CH₂—NHCOR²². In addition it is preferred if the residue-L-R³ isattached in meta-position of the aniline moiety of the general formulas(I), (II), (IV), (V), (VI) and (VIII).

Still more preferably are the compounds of general formula (III)

wherein-L-R³ represents —NO₂, —NH₂, —NH(CH₃), —NH(C₂H₅), —NH(C₃H₇), —N(CH₃)₂,—N(C₂H₅)₂, —N(C₃H₇)₂, —SO₂CH₃, —SO₂C₂H₅, —SO₂C₃H₇, —CONH₂, —CONH(CH₃),—CONH(C₂H₅), —CONH(C₃H₇), —CON(CH₃)₂, —CON(C₂H₅)₂, —CON(C₃H₇)₂,—NHCOCH₃, —NHCOC₂H₅, —NHCOC₃H₇, —NHSO₂NH₂, —NHSO₂NH(CH₃),—NHSO₂NH(C₂H₅), —NHSO₂NH(C₃H₇), —NHSO₂N(CH₃)₂, —NHSO₂N(C₂H₅)₂,—NHSO₂N(C₃H₇)₂, —NHSO₂CH₃, —NHSO₂C₂H₅, —NHSO₂C₃H₇, —NHCONH₂,—NHCONH(CH₃), —NHCONH(C₂H₅), —NHCONH(C₃H₇), —NHCON(CH₃)₂, —NHCON(C₂H₅)₂,—NHCON(C₃H₇)₂, —SO₂NH₂, —SO₂NH(CH₃), —SO₂NH(C₂H₅), —SO₂NH(C₃H₇),—SO₂N(CH₃)₂, —SO₂N(C₂H₅)₂, —SO₂N(C₃H₇)₂, —SO(NH)CH₃, —SO(NH)C₂H₅,—SO(NH)C₃H₇, —CH₂—NO₂, —CH₂—NH₂, —CH₂—NH(CH₃), —CH₂—NH(C₂H₅),—CH₂—NH(C₃H₇), —CH₂—N(CH₃)₂, —CH₂—N(C₂H₅)₂, —CH₂—N(C₃H₇)₂, —CH₂—SO₂CH₃,—CH₂—SO₂C₂H₅, —CH₂—SO₂C₃H₇, —CH₂—CONH₂, —CH₂—CONH(CH₃), —CH₂—CONH(C₂H₅),—CH₂—CONH(C₃H₇), —CH₂—CON(CH₃)₂, —CH₂—CON(C₂H₅)₂, —CH₂—CON(C₃H₇)₂,—CH₂—NHCOCH₃, —CH₂—NHCOC₂H₅, —CH₂—NHCOC₃H₇, —CH₂—NHSO₂NH₂,—CH₂—NHSO₂NH(CH₃), —CH₂—NHSO₂NH(C₂H₅), —CH₂—NHSO₂NH(C₃H₇),—CH₂—NHSO₂N(CH₃)₂, —CH₂—NHSO₂N(C₂H₅)₂, —CH₂—NHSO₂N(C₃H₇)₂,—CH₂—NHSO₂CH₃, —CH₂—NHSO₂C₂H₅, —CH₂—NHSO₂C₃H₇, —CH₂—NHCONH₂,—CH₂—NHCONH(CH₃), —CH₂—NHCONH(C₂H₅), —CH₂—NHCONH(C₃H₇),—CH₂—NHCON(CH₃)₂, —CH₂—NHCON(C₂H₅)₂, —CH₂—NHCON(C₃H₇)₂, —CH₂—SO₂NH₂,—CH₂—SO₂NH(CH₃), —CH₂—SO₂NH(C₂H₅), —CH₂—SO₂NH(C₃H₇), —CH₂—SO₂N(CH₃)₂,—CH₂—SO₂N(C₂H₅)₂, —CH₂—SO₂N(C₃H₇)₂, —CH₂—SO(NH)CH₃, —CH₂—SO(NH)C₂H₅,—CH₂—SO(NH)C₃H₇, —CH₂CH₂—NO₂, —CH₂CH₂—NH₂, —CH₂—CH₂—NH(CH₃),—CH₂—CH₂—NH(C₂H₅), —CH₂—CH₂—NH(C₃H₇), —CH₂—CH₂—N(CH₃)₂,—CH₂—CH₂—N(C₂H₅)₂, —CH₂—CH₂—N(C₃H₇)₂, —CH₂—CH₂—SO₂CH₃, —CH₂—CH₂—SO₂C₂H₅,—CH₂—CH₂—SO₂C₃H₇, —CH₂—CH₂—CONH₂, —CH₂—CH₂—CONH(CH₃),—CH₂—CH₂—CONH(C₂H₅), —CH₂—CH₂—CONH(C₃H₇), —CH₂—CH₂—CON(CH₃)₂,—CH₂—CH₂—CON(C₂H₅)₂, —CH₂—CH₂—CON(C₃H₇)₂, —CH₂—CH₂—NHCOCH₃,—CH₂—CH₂—NHCO₂H₅, —CH₂—CH₂—NHCO₃H₇, —CH₂—CH₂—NHSO₂NH₂,—CH₂—CH₂—NHSO₂NH(CH₃), —CH₂—CH₂—NHSO₂NH(C₂H₅), —CH₂—CH₂—NHSO₂NH(C₃H₇),—CH₂—CH₂—NHSO₂N(CH₃)₂, —CH₂—CH₂—NHSO₂N(C₂H₅)₂, —CH₂—CH₂—NHSO₂N(C₃H₇)₂,—CH₂—CH₂—NHSO₂CH₃, —CH₂—CH₂—NHSO₂C₂H₅, —CH₂—CH₂—NHSO₂C₃H₇,—CH₂—CH₂—NHCONH₂, —CH₂—CH₂—NHCONH(CH₃), —CH₂—CH₂—NHCONH(C₂H₅),—CH₂—CH₂—NHCONH(C₃H₇), —CH₂—CH₂—NHCON(CH₃)₂, —CH₂—CH₂—NHCON(C₂H₅)₂,—CH₂—CH₂—NHCON(C₃H₇)₂, —CH₂—CH₂—SO₂NH₂, —CH₂—CH₂—SO₂NH(CH₃),—CH₂—CH₂—SO₂NH(C₂H₅), —CH₂—CH₂—SO₂NH(C₃H₇)₂, —CH₂—CH₂—SO₂N(CH₃)₂,—CH₂—CH₂—SO₂N(C₂H₅)₂, —CH₂—CH₂—SO₂N(C₃H₇)₂, —CH₂—CH₂—SO(NH)CH₃,—CH₂—CH₂—SO(NH)C₂H₅, —CH₂—CH₂—SO(NH)C₃H₇, and whereinR² has the meanings as defined herein.

In general formulas (I), (IV), (V) and (VI) it is preferred that R⁴represents hydrogen.

Moreover it is especially preferred if the substituent-L-R³ represents—NO₂, —NH₂, —SO₂NH₂, —SO₂—NH—C(CH₃)₃, —SO₂CH₃, —CH₂—SO₂NH₂,—CH₂—SO₂—N(CH₃)₂, —CH₂—CH₂—SO₂NH₂, —NHSO₂CH₃, —NHCOCH₃, or—CH₂—SO₂—NH(CH₂CH₂CH₃).

Furthermore it is preferred if R⁵⁷ represents —NO₂, —CN, —F, —Cl, —Br,and it is more preferred if R⁵⁷ represents —NO₂, —F, —Cl, and it isespecially preferred if R⁵⁷ represents —F. Moreover in general formulas(I), (II), (III), (IV), (VI) and (VII) it is preferred if R⁵⁷ isattached in position 4 of the phenyl residue R² or in para position tothe linkage of the phenyl residue R² to the pyridyl ring or in metaposition to the substituent —B—Y—R⁵⁸—R⁵⁹.

The residue —B—Y—R⁵⁸—R⁵⁹ is most preferably an alkoxy group with 1 to 4carbon atoms and more preferably —OCH₃, —OC₂H₅, —OC₃H₇ or —OC₄H₉ andmost preferably —OCH₃.

R² is preferably 2-methoxyphenyl, 4-fluoro-2-methoxyphenyl, or6-fluoro-2-methoxyphenyl.

In yet another preferred embodiment of the present invention, thecompound according to the general formula (I) is selected from the groupof compounds depicted in the following Table 1.

TABLE 1 Compound No. Structure Nomenclature B1

4-(2-Methoxyphenyl)-N- phenylpyridin-2-amine C1

4-(2-Methoxyphenyl)-N-(3- nitrophenyl)pyridin-2-amine C2

4-(4-Fluoro-2- methoxyphenyl)-N-(3- nitrophenyl)pyridin-2-amine D1

3-[(4-(2- Methoxyphenyl)pyridin-2- yl)amino]benzenesulfon- amide D2

N-(tert-Butyl)-3-[(4-(4-fluoro- 2-methoxyphenyl)pyridin-2-yl)amino]benzenesulfon- amide E1

4-[(4-(2- Methoxyphenyl)pyridin-2- yl)amino]benzenesulfon- amide F1

4-(2-Methoxyphenyl)-N-(3- (methylsulfonyl)phenyl)- pyridin-2-amine G1

3-((4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)amino)phenylmethane-sulfonamide G2

[3-((4-(2- Methoxyphenyl)pyridin-2- yl)amino)phenyl]methane- sulfonamideG3

1-[3-((4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)amino)phenyl]-N,N-dimethylmethanesulfon- amide H1

2-[3-((4-(2- Methoxyphenyl)pyridin-2- yl)amino)phenylethane- sulfonamideI1

N¹-(4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)benzene-1,3-diamine J1

N-[3-((4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)amino)phenyl]methane-sulfonamide J2

N-[3-((4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)amino)phenyl]acetamideK1

1-[3-((4-(4-Fluoro-2- methoxyphenyl)pyridin-2- yl)amino)phenyl]-N-propylmethanesulfonamide

The compounds of the present invention may form salts with organic orinorganic acids or bases. Examples of suitable acids for such acidaddition salt formation are hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, acetic acid, citric acid, oxalic acid,malonic acid, salicylic acid, p-aminosalicylic acid, malic acid, fumaricacid, succinic acid, ascorbic acid, maleic acid, sulfonic acid,phosphonic acid, perchloric acid, nitric acid, formic acid, propionicacid, gluconic acid, lactic acid, tartaric acid, hydroxymaleic acid,pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid,p-hydroxybenzoic acid, methanesulfonic acid, ethanesulfonic acid,nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic acid,p-toluenesulfonic acid, naphthylsulfonic acid, sulfanilic acid,camphorsulfonic acid, china acid, mandelic acid, o-methylmandelic acid,hydrogen-benzenesulfonic acid, picric acid, adipic acid,d-o-tolyltartaric acid, tartronic acid, (o, m, p)-toluic acid,naphthylamine sulfonic acid, trifluoroacetic acid, and other mineral orcarboxylic acids well known to those skilled in the art. The salts areprepared by contacting the free base form with a sufficient amount ofthe desired acid to produce a salt in the conventional manner.

In the case the inventive compounds bear acidic groups, salts could alsobe formed with inorganic or organic bases. Examples for suitableinorganic or organic bases are, for example, NaOH, KOH, NH₄OH,tetraalkylammonium hydroxide, lysine or arginine and the like. Salts maybe prepared in a conventional manner using methods well known in theart, for example by treatment of a solution of the compound of thegeneral formula (I) with a solution of an acid, selected out of thegroup mentioned above.

Syntheses of Compounds

The synthesis of the inventive disubstituted pyridines according to thepresent invention is preferably carried out according to the generalsynthetic sequences, shown in Schemes 1 and 2.

In a first step a 2,4-dihalo-pyridine (II) is reacted with a boronicacid derivative (RO)₂B—R² to give 2-halo-pyridine intermediates (III).Preferred intermediates (II) are 4-bromo-2-chloro-pyridine or2-fluoro-4-iodo-pyridine. The boronic acid derivative may be a boronicacid (R═—H) or an ester of the boronic acid, e.g. its isopropyl ester(R═—CH(CH₃)₂), preferably an ester derived from pinacol in which theboronic acid intermediate forms a2-aryl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (R—R═—C(CH₃)₂—C(CH₃)₂—).

The coupling reaction is catalyzed by Pd catalysts, e.g. by Pd(0)catalysts like tetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄],tris(dibenzylideneacetone)-dipalladium(0) [Pd₂(dba)₃], or by Pd(II)catalysts like dichlorobis(triphenylphosphine)-palladium(II)[Pd(PPh₃)₂Cl₂], palladium(II) acetate in the presence oftriphenylphosphine or [1,1′-bis(diphenylphosphino)ferrocene]palladiumdichloride [Pd(dppf)Cl₂].

The reaction is preferably carried out by heating in a solvent likedioxane, DMF (dimethylformamide), DME (1,2-dimethoxyethane), THF(tetrahydrofuran), or isopropanol, more preferred in a mixture of such asolvent with water or with water and ethanol, and in the presence of abase like sodium bicarbonate, sodium carbonate, potassium carbonate, orK₃PO₄. Preferred methods use Pd(PPh₃)₄ in a mixture of DME and water inthe presence of potassium carbonate, Pd(PPh₃)₂Cl₂ in a mixture of DMEand water in the presence of potassium carbonate, or Pd(dppf)Cl₂ in amixture of dioxane and water in the presence of K₃PO₄. Heating may becarried out by a microwave oven.

The intermediates (III) may also be prepared by coupling of boronic acidderivatives (RO)₂B—R² with 4-halopyridines (IV), preferred with4-bromopyridine or 4-chloropyridine, followed by N-oxidation of theresulting 4-arylpyridine intermediate (V). Various methods to oxidizepyridines to its corresponding N-oxides are known to those skilled inthe art. Preferred methods use m-chloroperbenzoic acid (MCPBA) indichloromethane or hydrogenperoxide in the presence ofmethyltrioxorhenium(VII) as a catalyst. The resulting pyridine-N-oxide(VI) is heated with POCl₃ or POBr₃ to give the 2-chloro-pyridine or2-bromopyridine intermediates (III), respectively.

Disubstituted pyridines of Formula (I) are prepared by reaction of2-halopyridines (III) with an aniline H₂N—R¹. The reaction may becarried out without a catalyst (Method A) or in the presence of atransition metal catalyst, preferably in the presence of a Pd or Cucatalyst, e.g. CuI, more preferred in the presence of a Pd catalyst(Method B).

Reactions of Method A are preferably carried out with 2-fluoropyridines(Z¹═F) or with 2-chloropyridines (Z¹═Cl). Both reactants, the2-halopyridine (III) and the aniline H₂N—R¹ are heated at temperatureabove 80° C., preferably at a temperature of about 150° C. The reactionmay be carried out in an inert solvent like dioxane, DME, DMF, toluene,or xylene, optionally in the presence of an additional base like sodiumcarbonate, potassium carbonate, cesium carbonate, sodium hydride,triethylamine, N,N-diisopropylethylamine, NaOC(CH₃)₃, KOC(CH₃)₃, orKN(Si(CH₃)₃)₂. Preferably it is carried out by heating in a microwaveoven at a temperature of about 150° C., either neat without a solventand without an additional base or in DMF in the presence of cesiumcarbonate.

Reactions according to Method B are preferably carried out with2-chloropyridines (Z¹═Cl) or with 2-bromopyridines (Z¹═Br). Pd catalystsare selected from Pd(0) catalysts liketetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄],tris(dibenzylideneacetone)dipalladium(0) [Pd₂(dba)₃], or from Pd(II)catalysts like dichlorobis(triphenylphosphine)palladium(II)[Pd(PPh₃)₂Cl₂], palladium(II) chloride, palladium(II)acetate, ordichlorobis(acetonitrile)palladium(II) [PdCl₂(CH₃CN)₂], preferably inthe presence of an additional phosphine ligand. The reaction is carriedout in an inert solvent like DMF, toluene, xylene, dioxane, or DME andin the presence of a base like sodium hydride, sodium carbonate, cesiumcarbonate, NaOC(CH₃)₃, or KOC(CH₃)₃. Preferred methods which employPd₂(dba)₃ as a catalyst use heating in xylene, toluene, DMF, or dioxanein the presence of ligands like([1,1′-biphenyl]-2-yl)dicyclohexylphosphine,2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane,dicyclohexyl-[2′-(dimethylamino)biphenyl-2-yl]phosphine, or1,1′-bis(diphenylphosphino)ferrocene and a base like NaOC(CH₃)₃; whichemploy palladium(II) acetate use heating in toluene, xylene, or DMF inthe presence of 2,2′-bis(diphenylphosphino)biphenyl or[1,1′-binaphthalene]-2,2′-diyl-bis(diphenylphosphine) [BINAP] and a baselike NaOC(CH₃)₃; which employ palladium(II)chloride use heating intoluene or xylene in the presence of4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos] and a baselike NaOC(CH₃)₃; which employ PdCl₂(CH₃CN)₂ use heating in DMF in thepresence of a ligand like4,5-bis(diphenylphosphino)-9,9-dimethylxanthene [Xantphos],[1,1′-binaphthalene]-2,2′-diyl-bis(3,5-xylyl-phosphine)[(R)-3,5-xylyl-BINAP],2-(dicyclohexylphosphino)-2′,6′-di-isopropoxy-1,1′-biphenyl [Ruphos], or2-(dicyclohexylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl [Xphos]and a base like NaOC(CH₃)₃. In a more preferred method the couplingreaction is carried out by heating in DMF with PdCl₂(CH₃CN)₂ andXantphos in the presence of NaOC(CH₃)₃.

The synthesis of pyridines of Formula (I) may be carried out in theinverse order of the reaction steps compared to Scheme 1, in such amanner that in a first step a 2,4-dihalo-pyridine (II) is reacted withan aniline H₂N—R¹ followed in a second step by the reaction of theintermediate pyridine (VII) with a boronic acid derivative (RO)₂B—R².The sequence may be carried out without isolation of the intermediatepyridine (VII).

Several compounds of Formula (I) may be prepared by convertingsubstituents which are attached to the aromatic rings R¹ and/or R² toother substituents using standard reactions which are known to theperson skilled in the art. For example, a nitro group can be reduced toan amino group, such an amino group can be converted to a sulfonamide byreaction with a sulfonyl chloride, to a carboxamide by reaction with acarbonyl chloride or another activated derivative of a carboxylic acid,to an urea by reaction with an isocyanate. Carbamate substituents may becleaved to amino groups, in particular tert-butyl carbamates by reactionwith acids like trifluoroacetic acid or hydrochloric acid. Formyl groupsmay be converted to aminomethyl groups by reaction with primary aminesunder conditions of a reductive amination. Benzylic N,N-dialkyl- orN-monoalkyl-sulfonamides may be prepared by reaction of a correspondingN-substituted sulfonamide, preferably of a N,N-dimethyl-, aN,N-diphenyl-, or a N-methyl-N-phenyl-sulfonamide, with a primary orsecondary amine, respectively.

In a further aspect of the present invention, the novel compoundsaccording to the general formula (I) are used as pharmaceutically activeagent.

Pharmaceutical Compositions and Drug Combinations

Another aspect of the present invention relates to drug combinations andpharmaceutical compositions comprising at least one compound of generalformula (I) as active ingredient together with at least onepharmaceutically acceptable carrier, excipient and/or diluent andoptionally together with one or more other anti-tumor agents or with oneor more anti-retroviral drugs. As used herein the term “drugcombination” refers to a combination of at least to pharmaceuticallyactive agents or therapeutic agents with or without further ingredients,carrier, diluents and/or solvents. As used herein the term“pharmaceutical composition” refers to a galenic formulation of at leastone pharmaceutically active agent together with at least one furtheringredient, carrier, diluent and/or solvent.

Compounds of formula (I) may be administered as the sole pharmaceuticalagent or in combination with one or more additional therapeutic agents,wherein the drug combination causes no unacceptable adverse effects.This combination therapy includes administration of a singlepharmaceutical dosage formulation, which contains a compound of formula(I) and one or more additional therapeutic agents in form of a singlepharmaceutical composition, as well as administration of the compound offormula (I) and each additional therapeutic agent in its own separatepharmaceutical dosage formulation, i.e. in its own separatepharmaceutical composition. For example, a compound of formula (I) and atherapeutic agent may be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent may be administered in separate pharmaceutical compositions.

Where separate pharmaceutical compositions are used, the compound offormula (I) and one or more additional therapeutic agents may beadministered at essentially the same time (e.g., concurrently) or atseparately staggered times (e.g., sequentially).

In particular, the compounds of the present invention may be used infixed or separate pharmaceutical compositions with other anti-tumoragents such as alkylating agents, anti-metabolites, plant-derivedanti-tumor agents, hormonal therapy agents, topoisomerase inhibitors,camptothecin derivatives, kinase inhibitors, targeted drugs, antibodies,interferons and/or biological response modifiers, anti-angiogeniccompounds, and other anti-tumor drugs. In this regard, the following isa non-limiting list of examples of secondary agents that may be used incombination with the compounds of the present invention:

-   -   Alkylating agents include, but are not limited to, nitrogen        mustard N-oxide, cyclophosphamide, ifosfamide, thiotepa,        ranimustine, nimustine, temozolomide, altretamine, apaziquone,        brostallicin, bendamustine, carmustine, estramustine,        fotemustine, glufosfamide, mafosfamide, and mitolactol;        platinum-coordinated alkylating compounds include, but are not        limited to, cisplatin, carboplatin, eptaplatin, lobaplatin,        nedaplatin, oxaliplatin, and satraplatin;    -   Anti-metabolites include, but are not limited to, methotrexate,        6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil alone        or in combination with leucovorin, tegafur, doxifluridine,        carmofur, cytarabine, cytarabine ocfosfate, enocitabine,        gemcitabine, fludarabin, 5-azacitidine, capecitabine,        cladribine, clofarabine, decitabine, eflornithine,        ethynylcytidine, cytosine arabinoside, hydroxyurea, melphalan,        nelarabine, nolatrexed, ocfosfite, disodium premetrexed,        pentostatin, peliterxol, raltitrexed, triapine, trimetrexate,        vidarabine, vincristine, and vinorelbine;    -   Hormonal therapy agents include, but are not limited to,        exemestane, Lupron, anastrozole, doxercalciferol, fadrozole,        formestane, 11-beta hydroxysteroid dehydrogenase 1 inhibitors,        17-alpha hydroxylase/17,20 lyase inhibitors such as abiraterone        acetate, 5-alpha reductase inhibitors such as finasteride and        epristeride, anti-estrogens such as tamoxifen citrate and        fulvestrant, Trelstar, toremifene, raloxifene, lasofoxifene,        letrozole, anti-androgens such as bicalutamide, flutamide,        mifepristone, nilutamide, Casodex, and anti-progesterones and        combinations thereof;    -   Plant-derived anti-tumor substances include, e.g., those        selected from mitotic inhibitors, for example epothilones such        as sagopilone, ixabepilone and epothilone B, vinblastine,        vinflunine, docetaxel, and paclitaxel;    -   Cytotoxic topoisomerase inhibiting agents include, but are not        limited to, aclarubicin, doxorubicin, amonafide, belotecan,        camptothecin, 10-hydroxycam ptothecin, 9-aminocam ptothecin,        diflomotecan, irinotecan, topotecan, edotecarin, epimbicin,        etoposide, exatecan, gimatecan, lurtotecan, mitoxantrone,        pirambicin, pixantrone, rubitecan, sobuzoxane, tafluposide, and        combinations thereof;    -   Immunologicals include interferons such as interferon alpha,        interferon alpha-2a, interferon alpha-2b, interferon beta,        interferon gamma-1a and interferon gamma-n1, and other immune        enhancing agents such as L19-IL2 and other IL2 derivatives,        filgrastim, lentinan, sizofilan, TheraCys, ubenimex,        aldesleukin, alemtuzumab, BAM-002, dacarbazine, daclizumab,        denileukin, gemtuzumab, ozogamicin, ibritumomab, imiquimod,        lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim,        sargramostim, tasonermin, tecleukin, thymalasin, tositumomab,        Vimlizin, epratuzumab, mitumomab, oregovomab, pemtumomab, and        Provenge; Merial melanoma vaccine;    -   Biological response modifiers are agents that modify defense        mechanisms of living organisms or biological responses such as        survival, growth or differentiation of tissue cells to direct        them to have anti-tumor activity; such agents include, e.g.,        krestin, lentinan, sizofiran, picibanil, ProMune, and ubenimex;    -   Anti-angiogenic compounds include, but are not limited to,        acitretin, aflibercept, angiostatin, aplidine, asentar,        axitinib, recentin, bevacizumab, brivanib alaninat, cilengtide,        combretastatin, DAST, endostatin, fenretinide, halofuginone,        pazopanib, ranibizumab, rebimastat, removab, revlimid,        sorafenib, vatalanib, squalamine, sunitinib, telatinib,        thalidomide, ukrain, and vitaxin;    -   Antibodies include, but are not limited to, trastuzumab,        cetuximab, bevacizumab, rituximab, ticilimumab, ipilimumab,        lumiliximab, catumaxomab, atacicept, oregovomab, and        alemtuzumab;    -   VEGF inhibitors such as, e.g., sorafenib, DAST, bevacizumab,        sunitinib, recentin, axitinib, aflibercept, telatinib, brivanib        alaninate, vatalanib, pazopanib, and ranibizumab; Palladia    -   EGFR (HER1) inhibitors such as, e.g., cetuximab, panitumumab,        vectibix, gefitinib, erlotinib, and Zactima;    -   HER2 inhibitors such as, e.g., lapatinib, tratuzumab, and        pertuzumab;    -   mTOR inhibitors such as, e.g., temsirolimus,        sirolimus/Rapamycin, and everolimus;    -   c-Met inhibitors;    -   PI3K and AKT inhibitors;    -   CDK inhibitors such as roscovitine and flavopiridol;    -   Spindle assembly checkpoints inhibitors and targeted        anti-mitotic agents such as PLK inhibitors, Aurora inhibitors        (e.g. Hesperadin), checkpoint kinase inhibitors, and KSP        inhibitors;    -   HDAC inhibitors such as, e.g., panobinostat, vorinostat, MS275,        belinostat, and LBH589;    -   HSP90 and HSP70 inhibitors;    -   Proteasome inhibitors such as bortezomib and carfilzomib;    -   Serine/threonine kinase inhibitors including MEK inhibitors        (such as e.g. RDEA 119) and Raf inhibitors such as sorafenib;    -   Farnesyl transferase inhibitors such as, e.g., tipifarnib;    -   Tyrosine kinase inhibitors including, e.g., dasatinib,        nilotibib, DAST, bosutinib, sorafenib, bevacizumab, sunitinib,        AZD2171, axitinib, aflibercept, telatinib, imatinib mesylate,        brivanib alaninate, pazopanib, ranibizumab, vatalanib,        cetuximab, panitumumab, vectibix, gefitinib, erlotinib,        lapatinib, tratuzumab, pertuzumab, and c-Kit inhibitors;        Palladia, masitinib    -   Vitamin D receptor agonists;    -   Bcl-2 protein inhibitors such as obatoclax, oblimersen sodium,        and gossypol;    -   Cluster of differentiation 20 receptor antagonists such as,        e.g., rituximab;    -   Ribonucleotide reductase inhibitors such as, e.g., gemcitabine;    -   Tumor necrosis apoptosis inducing ligand receptor 1 agonists        such as, e.g., mapatumumab;    -   5-Hydroxytryptamine receptor antagonists such as, e.g., rEV598,        xaliprode, palonosetron hydrochloride, granisetron, Zindol, and        AB-1001;    -   Integrin inhibitors including alpha5-beta1 integrin inhibitors        such as, e.g., E7820, JSM 6425, volociximab, and endostatin;    -   Androgen receptor antagonists including, e.g., nandrolone        decanoate, fluoxymesterone, Android, Prost-aid, andromustine,        bicalutamide, flutamide, apo-cyproterone, apo-flutamide,        chlormadinone acetate, Androcur, Tabi, cyproterone acetate, and        nilutamide;    -   Aromatase inhibitors such as, e.g., anastrozole, letrozole,        testolactone, exemestane, aminoglutethimide, and formestane;    -   Matrix metalloproteinase inhibitors;    -   Other anti-cancer agents including, e.g., alitretinoin,        ampligen, atrasentan bexarotene, bortezomib, bosentan,        calcitriol, exisulind, fotemustine, ibandronic acid,        miltefosine, mitoxantrone, I-asparaginase, procarbazine,        dacarbazine, hydroxycarbamide, pegaspargase, pentostatin,        tazaroten, velcade, gallium nitrate, canfosfamide, darinaparsin,        and tretinoin.

The compounds of the present invention may also be employed in cancertreatment in conjunction with radiation therapy and/or surgicalintervention.

Further aspects of the present invention relate to the use of thecompounds of general formula (I) for the preparation of a pharmaceuticalcomposition useful for prophylaxis and/or treatment of infectiousdiseases including opportunistic diseases, immunological diseases,autoimmune diseases, cardiovascular diseases, cell proliferativediseases, inflammation, erectile dysfunction and stroke.

Another preferred embodiment of the invention refers to a compoundaccording to the general formula (I) for the preparation of apharmaceutical composition for the prophylaxis and/or treatment ofinfectious diseases, including opportunistic diseases, immunologicaldiseases, autoimmune diseases, cardiovascular diseases, cellproliferative diseases, inflammation, erectile dysfunction and stroke.

Infectious Diseases Including Opportunistic Infections

In yet another aspect of the present invention, the compounds accordingto the general formula (I) are for the preparation of a pharmaceuticalcomposition for the prophylaxis and/or treatment of infectious diseases,including opportunistic diseases and opportunistic infections. The terminfectious diseases comprises infections caused by viruses, bacteria,prions, fungi, and/or parasites.

Especially, virally induced infectious diseases, including opportunisticdiseases are addressed. In a preferred embodiment of this aspect, thevirally induced infectious diseases, including opportunistic diseases,are caused by retroviruses, human endogenous retroviruses (HERVs),hepadnaviruses, herpesviruses, flaviviridae, and/or adenoviruses.Preferably, the retroviruses are selected from lentiviruses oroncoretroviruses, wherein the lentivirus is preferably selected from thegroup comprising: HIV-1, HIV-2, feline immunodeficiency virus (FIV),bovine immunodeficiency virus (BIV), sivian immunodeficiency viruses(SIVs), chimeras of HIV and SIV (SHIV), caprine arthritis encephalitisvirus (CAEV), visna/maedi virus (VMV) or equine infectious anemia virus(EIAV), preferably HIV-1 and HIV-2, and the oncoretrovirus is preferablyselected from HTLV-I, HTLV-II or bovine leukemia virus (BLV), preferablyHTLV-I and HTLV-II.

The hepadnavirus is preferably selected from HBV, ground squirrelhepatitis virus (GSHV) or woodchuck hepatitis virus (WHV), preferablyHBV, the herpesvirus is selected from the group comprising: Herpessimplex virus I (HSV I), herpes simplex virus II (HSV II), Epstein-Barrvirus (EBV), varicella zoster virus (VZV), human cytomegalovirus (HCMV)or human herpesvirus 8 (HHV-8), preferably HCMV, and the flaviviridae isselected from HCV, West nile or Yellow Fever.

It is to be understood, that all the viruses mentioned above, alsocomprise drug resistant virus strains.

Examples of infective diseases are AIDS, Alveolar Hydatid Disease (AHD,Echinococcosis), Amebiasis (Entamoeba histolytica Infection),Angiostrongylus Infection, Anisakiasis, Anthrax, Babesiosis (BabesiaInfection), Balantidium Infection (Balantidiasis), BaylisascarisInfection (Raccoon Roundworm), Bilharzia (Schistosomiasis), Blastocystishominis Infection (Blastomycosis), Boreliosis, Botulism, BrainerdDiarrhea, Brucellosis, BSE (Bovine Spongiform Encephalopathy),Candidiasis, Capillariasis (Capillaria Infection), CFS (Chronic FatigueSyndrome), Chagas Disease (American Trypanosomiasis), Chickenpox(Varicella-Zoster virus), Chlamydia pneumoniae Infection, Cholera,Chronic Fatigue Syndrome, CJD (Creutzfeldt-Jakob Disease), Clonorchiasis(Clonorchis Infection), CLM (Cutaneous Larva Migrans, HookwormInfection), Coccidioidomycosis, Conjunctivitis, Coxsackievirus A16(Hand, Foot and Mouth Disease), Cryptococcosis, CryptosporidiumInfection (Cryptosporidiosis), Culex mosquito (Vector of West NileVirus), Cutaneous Larva Migrans (CLM), Cyclosporiasis (CyclosporaInfection), Cysticercosis (Neurocysticercosis), CytomegalovirusInfection, Dengue/Dengue Fever, Dipylidium Infection (Dog and Cat FleaTapeworm), Ebola Virus Hemorrhagic Fever, Echinococcosis (AlveolarHydatid Disease), Encephalitis, Entomoeba coli Infection, Entomoebadispar Infection, Entomoeba hartmanni Infection, Entomoeba histolyticaInfection (Amebiasis), Entomoeba polecki Infection, Enterobiasis(Pinworm Infection), Enterovirus Infection (Non-Polio), Epstein-BarrVirus Infection, Escherichia coli Infection, Foodborne Infection, Footand mouth Disease, Fungal Dermatitis, Gastroenteritis, Group Astreptococcal Disease, Group B streptococcal Disease, Hansen's Disease(Leprosy), Hantavirus Pulmonary Syndrome, Head Lice Infestation(Pediculosis), Helicobacter pylori Infection, Hematologic Disease,Hendra Virus Infection, Hepatitis (HCV, HBV), Herpes Zoster (Shingles),HIV Infection, Human Ehrlichiosis, Human Parainfluenza Virus Infection,Influenza, Isosporiasis (Isospora Infection), Lassa Fever,Leishmaniasis, Kala-azar (Kala-azar, Leishmania Infection), Leprosy,Lice (Body lice, Head lice, Pubic lice), Lyme Disease, Malaria, MarburgHemorrhagic Fever, Measles, Meningitis, Mosquito-borne Diseases,Mycobacterium avium Complex (MAC) Infection, Naegleria Infection,Nosocomial Infections, Nonpathogenic Intestinal Amebae Infection,Onchocerciasis (River Blindness), Opisthorciasis (OpisthorcisInfection), Parvovirus Infection, Plague, PCP (Pneumocystis cariniiPneumonia), Polio, Q Fever, Rabies, Respiratory Syncytial Virus (RSV)Infection, Rheumatic Fever, Rift Valley Fever, River Blindness(Onchocerciasis), Rotavirus Infection, Roundworms Infection,Salmonellosis, Salmonella Enteritidis, Scabies, Shigellosis, Shingles,Sleeping Sickness, Smallpox, Streptococcal Infection, Tapeworm Infection(Taenia Infection), Tetanus, Toxic Shock Syndrome, Tuberculosis, Ulcers(Peptic Ulcer Disease), Valley Fever, Vibrio parahaemolyticus Infection,Vibrio vulnificus Infection, Viral Hemorrhagic Fever, Warts, Waterborneinfectious Diseases, West Nile Virus Infection (West Nile Encephalitis),Whooping Cough, Yellow Fever.

Immunological Diseases

Another aspect of the present invention is directed to the use of atleast one compound of the general formula (I) and/or pharmaceuticallyacceptable salts thereof for prophylaxis and/or treatment ofimmunological diseases, neuroimmunological diseases, and autoimmunediseases.

Immunological diseases are, for instance, asthma and diabetes, rheumaticand autoimmune diseases, AIDS, rejection of transplanted organs andtissues (cf. below), rhinitis, chronic obstructive pulmonary diseases,osteoporisis, ulcerative colitis, sinusitis, lupus erythematosus,recurrent infections, atopic dermatitis/eczema and occupationalallergies, food allergies, drug allergies, severe anaphylacticreactions, anaphylaxis, and other manifestations of allergic disease, aswell as uncommon problems such as primary immunodeficiencies, includingantibody deficiency states, cell mediated immunodeficiencies (e.g.,severe combined immunodeficiency, DiGeorge syndrome, Hyper-IgE syndrome,Wiskott-Aldrich syndrome, ataxia-telangiectasia), immune mediatedcancers, and white cell defects.

In autoimmune diseases, such as systemic lupus erythematosus, rheumatoidarthritis (RA), multiple sclerosis (MS), immune-mediated or type 1diabetes mellitus, immune mediated glomerulonephritis, scleroderma,pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myastheniagravis, inflammatory bowel diseases, Crohn's disease, psoriasis,autoimmune thyroid diseases, and Hashimoto's disease, dermatomyositis,goodpastture syndrome, myasthenia gravis pseudoparalytica, ophtalmiasympatica, phakogene uveitis, chronical agressivce hepatitis, primarybilliary cirrhosis, autoimunehemolytic anemy, Werlof disease, specificcells uncontrollably attack the body's own tissues and organs(autoimmunity), producing inflammatory reactions and other serioussymptoms and diseases.

Hashimoto's thyroiditis is one of the most common autoimmune diseases.“Autoimmune disease” refers to a category of more than 80 chronicillnesses, each very different in nature, that can affect everythingfrom the endocrine glands (like the thyroid) to organs like the kidneys,as well as to the digestive system.

There are many different autoimmune diseases, and they can each affectthe body in different ways. For example, the autoimmune reaction isdirected against the brain in multiple sclerosis and the gut in Crohn'sdisease. In other autoimmune diseases such as systemic lupuserythematosus (lupus), affected tissues and organs may vary amongindividuals with the same disease. One person with lupus may haveaffected skin and joints whereas another may have affected skin, kidney,and lungs. Ultimately, damage to certain tissues by the immune systemmay be permanent, as with destruction of insulin-producing cells of thepancreas in Type 1 diabetes mellitus.

Cardiovascular Diseases

The inventive compounds are also useful for prophylaxis and/or treatmentof cardiovascular diseases such as cardiac hypertrophy, adult congenitalheart disease, aneurysm, stable angina, unstable angina, anginapectoris, angioneurotic edema, aortic valve stenosis, aortic aneurysm,arrhythmia, arrhythmogenic right ventricular dysplasia,arteriosclerosis, arteriovenous malformations, atrial fibrillation,Behcet syndrome, bradycardia, cardiac tamponade, cardiomegaly,congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictivecardiomyopathy, cardiovascular disease prevention, carotid stenosis,cerebral hemorrhage, Churg-Strauss syndrome, diabetes, Ebstein'sAnomaly, Eisenmenger complex, cholesterol embolism, bacterialendocarditis, fibromuscular dysplasia, congenital heart defects, heartdiseases, congestive heart failure, heart valve diseases, heart attack,epidural hematoma, hematoma, subdural, Hippel-Lindau disease, hyperemia,hypertension, pulmonary hypertension, hypertrophic growth, leftventricular hypertrophy, right ventricular hypertrophy, hypoplastic leftheart syndrome, hypotension, intermittent claudication, ischemic heartdisease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome,long QT syndrome mitral valve prolapse, moyamoya disease, mucocutaneouslymph node syndrome, myocardial infarction, myocardial ischemia,myocarditis, pericarditis, peripheral vascular diseases, phlebitis,polyarteritis nodosa, pulmonary atresia, Raynaud disease, restenosis,Sneddon syndrome, stenosis, superior vena cava syndrome, syndrome X,tachycardia, Takayasu's arteritis, hereditary hemorrhagictelangiectasia, telangiectasis, temporal arteritis, tetralogy of fallot,thromboangiitis obliterans, thrombosis, thromboembolism, tricuspidatresia, varicose veins, vascular diseases, vasculitis, vasospasm,ventricular fibrillation, Williams syndrome, peripheral vasculardisease, varicose veins and leg ulcers, deep vein thrombosis,Wolff-Parkinson-White syndrome.

Preferred are cardiac hypertrophy, adult congenital heart disease,aneurysms, angina, angina pectoris, arrhythmias, cardiovascular diseaseprevention, cardiomyopathies, congestive heart failure, myocardialinfarction, pulmonary hypertension, hypertrophic growth, restenosis,stenosis, thrombosis and arteriosclerosis.

Proliferative Disease

In yet another preferred embodiment, the cell proliferative disease iscancer, which is preferably selected from the group comprising orconsisting of:

The proliferation disorders and cancers are preferably selected from thegroup comprising or consisting of adenocarcinoma, choroidal melanoma,acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma,astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor,bladder cancer, bronchial carcinoma, breast cancer, Burkitt's lymphoma,corpus cancer, CUP-syndrome (carcinoma of unknown primary), colorectalcancer, small intestine cancer, small intestinal tumors, ovarian cancer,endometrial carcinoma, ependymoma, epithelial cancer types, Ewing'stumors, gastrointestinal tumors, gastric cancer, gallbladder cancer,gall bladder carcinomas, uterine cancer, cervical cancer, cervix,glioblastomas, gynecologic tumors, ear, nose and throat tumors,hematologic neoplasias, hairy cell leukemia, urethral cancer, skincancer, skin testis cancer, brain tumors (gliomas), brain metastases,testicle cancer, hypophysis tumor, carcinoids, Kaposi's sarcoma,laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma,head and neck tumors (tumors of the ear, nose and throat area), coloncarcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area andon lips), cancer of the central nervous system, liver cancer, livermetastases, leukemia, eyelid tumor, lung cancer, lymph node cancer(Hodgkin's/Non-Hodgkin's lymphomas), lymphomas, stomach cancer,malignant melanoma, malignant neoplasia, malignant tumorsgastrointestinal tract, breast carcinoma, rectal cancer,medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosisfungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renalcell carcinomas, non-Hodgkin's lymphomas, oligodendroglioma, esophagealcarcinoma, osteolytic carcinomas and osteoplastic carcinomas,osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer,plasmocytoma, prostate cancer, pharyngeal cancer, rectal carcinoma,retinoblastoma, vaginal cancer, thyroid carcinoma, Schneeberger disease,esophageal cancer, spinalioms, T-cell lymphoma (mycosis fungoides),thymoma, tube carcinoma, eye tumors, urethral cancer, urologic tumors,urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors,soft tissue sarcoma, Wilm's tumor, cervical carcinoma, tongue cancer,invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinomain situ, lobular carcinoma in situ, small-cell lung carcinoma,non-small-cell lung carcinoma, bronchial adenoma, pleuropulmonaryblastoma, mesothelioma, brain stem glioma, hypophtalmic glioma,cerebellar astrocytoma, cerebral astrocytoma, neuroectodermal tumours,pineal tumors, sarcoma of the uterus, salivary gland cancers, anal glandadenocarcinomas, mast cell tumors, pelvis tumours, ureter tumours,hereditary papillary renal cancers, sporadic papillary renal cancers,intraocular melanoma, hepatocellular carcinoma (liver cell carcinomaswith or without fibrolamellar variant), cholangiocarcinoma (intrahepaticbile duct carcinoma), mixed hepatocellular cholangiocarcinoma, squamouscell carcinoma, malignant melanoma, Merkel cell skin cancer,non-melanoma skin cancer, hypopharyngeal cancer, nasopharyngeal cancer,oropharyngeal cancer, oral cavity cancer, squamous cell cancer, oralmelanoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, lymphoma ofthe central nervous system, malignant fibrous histiocytoma,lymphosarcoma, rhabdomyosarcoma, malignant histiocytosis, fibrosarcoma,hemangiosarcoma, hemangiopericytoma, leiomyosarcoma, canine mammarycarcinoma, and feline mammary carcinoma.

Preferred are the following cancer types: Leukemias including but notlimited to chronic lymphocytic leukemia, chronic myelogenous leukemia,acute lymphoblastic leukemia, acute myeloid leukemia, mixed lineageleukemia, bladder cancer, breast cancer, breast carcinoma, cancer of thecentral nervous system, colon carcinoma, gastric cancer, lung cancer,kidney cancer, melanoma, head and neck tumors (tumors of the ear, noseand throat area), ovarian cancer, ovarial carcinoma, cervical cancer,cervix, cervical carcinoma, glioblastomas, pancreatic cancer, pancreaticcarcinoma, prostate cancer, stomach cancer, skin cancer, skin testiscancer, Hodgkin's lymphoma, liver cancer, liver metastases and renalcell carcinomas.

Inflammation

In yet another preferred embodiment, said inflammation is mediatedpreferably by the cytokines TNF-α, IL-1β, GM-CSF, IL-6 and/or IL-8.

As described above, the compounds according to general formula (I) arepharmaceutically active agents for prophylaxis and/or treatment ofinflammatory diseases. Thus, these compounds are used for themanufacture of a pharmaceutical formulation for prophylaxis and/ortreatment of inflammations and inflammatory diseases in mammals,including humans.

Inflammatory diseases can emanate from infectious and non-infectiousinflammatory conditions which may result from infection by an invadingorganism or from irritative, traumatic, metabolic, allergic, autoimmune,or idiopathic causes as shown in the following list.

I. Acute infections

A. Viral B. BacterialII. Noninfectious causesIII. Chronic (granulomatous) diseases

A. Bacterial B. Spirochetal C. Mycotic (Fungal) D. IdiopathicIV. Allergic, immune, and idiopathic disorders

-   -   A. Hypersensitivity reactions    -   B. Immune and idiopathic disorders        V. Miscellaneous inflammatory conditions    -   A. Parasitic infections    -   B. Inhalation causes: —Acute (thermal) injury        -   —Pollution and inhalant allergy        -   —Carcinogens    -   C. Radiation injury: —Radionecrosis

Thus, the compounds disclosed herein can be used for prophylaxis and/ortreatment of inflammations caused by invading organisms such as viruses,bacteria, prions, and parasites as well as for prophylaxis and/ortreatment of inflammations caused by irritative, traumatic, metabolic,allergic, autoimmune, or idiopathic reasons.

Consequently, the disclosed compounds are useful for prophylaxis and/ortreatment of inflammatory diseases which are initiated or caused byviruses, parasites, and bacteria which are connected to or involved ininflammations.

The following bacteria are known to cause inflammatory diseases:mycoplasma pulmonis (causes e.g. chronic lung diseases (CLD), murinechronic respiratory disease), ureaplasma urealyticum (causes pneumoniain newborns), mycoplasma pneumoniae and chlamydia pneumoniae (causechronic asthma), C. pneumoniae (causes atherosclerosis, pharyngitis topneumonia with empyema, human coronary heart disease), Helicobacterpylori (human coronary heart disease, stomach ulcers). The followingviruses are known to cause inflammatory diseases: herpesvirusesespecially cytomegalovirus (causes human coronary heart disease).

The compounds disclosed herein are useful for prophylaxis and/ortreatment of inflammatory diseases caused and/or induced and/orinitiated and/or enhanced by the afore-mentioned bacteria or viruses.

Furthermore, the compounds of formula (I) are useful for prophylaxisand/or treatment of inflammatory diseases of the central nervous system(CNS), inflammatory rheumatic diseases, inflammatory diseases of bloodvessels, inflammatory diseases of the middle ear, inflammatory boweldiseases, inflammatory diseases of the skin, inflammatory diseaseuveitis, inflammatory diseases of the larynx.

Examples for inflammatory diseases of the central nervous system (CNS)are algal disorders, protothecosis, bacterial disorders, abscessation,bacterial meningitis, idiopathic inflammatory disorders, eosinophilicmeningoencephalitis, feline polioencephalomyelitis, granulomatousmeningoencephalomyelitis, meningitis, steroid responsivemeningitis-arteritis, miscellaneous meningitis/meningoencephalitis,meningoencephalitis in greyhounds, necrotizing encephalitis,pyogranulomatous meningoencephalomyelitis, shaker dog disease, mycoticdiseases of the CNS, parasitic encephalomyelitis, prion protein induceddiseases, feline spongiform encephalopathy, protozoalencephalitis-encephalomyelitis, toxoplasmosis, neosporosis,sarcocystosis, encephalitozoonosis, trypanosomiasis, acanthamebiasis,babesiosis, leishmaniasis, rickettsial disorders, rocky mountain spottedfever, canine ehrlichiosis, salmon poisoning, viral disorders,aujeszky's disease, borna disease, canine herpes virusencephalomyelitis, canine distemper encephalomyelitis, canine distemperencephalomyelitis in immature animals, chronic relapsingencephalomyelitis, post-vaccinal canine distemper encephalitis, felineimmunodeficiency virus, feline infectious peritonitis, feline leukemiavirus, infectious canine hepatitis, La Crosse virus encephalitis,parvovirus encephalitis, rabies, post-vaccinal rabies.

Examples for inflammatory rheumatic diseases are rheumatoid arthritis,scleroderma, lupus, polymyositis, dermatomyositis, psoriatic arthritis,ankylosing spondylitis, Reiters's syndrome, juvenile rheumatoidarthritis, bursitis, tendinitis (tendonitis), and fibromyositis.

Examples for inflammatory diseases of blood vessels are vasculitis,autoantibodies in vasculitis, microscopic polyangiitis, giant cellarteritis, Takayasu's arteritis, vasculitis of the central nervoussystem, thromboangiitis obliterans (Buerger's Disease), vasculitissecondary to bacterial, fungal, and parasitic infection, vasculitis andrheumatoid arthritis, vasculitis in systemic lupus erythematosus,vasculitis in the idiopathic inflammatory myopathies, relapsingpolychondritis, systemic vasculitis in sarcoidosis, vasculitis andmalignancy, and drug-induced vasculitis.

Examples for inflammatory diseases of the middle ear are acutesuppurative otitis media, bullous myringitis, granular myringitis, andchronic suppurative otitis media, which can manifest as mucosal disease,cholesteatoma, or both.

Examples for inflammatory bowel diseases are ulcerative colitis, Crohn'sdisease.

Examples for inflammatory diseases of the skin are acute inflammatorydermatoses, urticaria (hives), spongiotic dermatitis, allergic contactdermatitis, irritant contact dermatitis, atopic dermatitis, erythemalmultiforme (EM minor), Stevens-Johnson syndrome (SJS, EM major), toxicepidermal necrolysis (TEN), chronic inflammatory dermatoses, psoriasis,lichen planus, discoid lupus erythematosus, and acne vulgaris.

Uveitis are inflammations located in and/or on the eye and may beassociated with inflammation elsewhere in the body. In mostcircumstances, patients who have uveitis as part of a disease elsewherein the body are aware of that illness. The majority of patients withuveitis do not have an apparent associated systemic illness. Causes ofuveitis can be infectious causes, masquerade syndromes, suspectedimmune-mediated diseases, and/or syndromes confined primarily to theeye.

The following viruses are associated with inflammations: humanimmunodeficiency virus-I, herpes simplex virus, herpes zoster virus, andcytomegalovirus.

Bacterial or spirochetal caused, induced, initiated and/or enhancedinflammations are tuberculosis, leprosy, proprionobacterium, syphilis,Whipple's disease, leptospirosis, brucellosis, and lyme disease.

Parasitic (protozoan or helminthic) caused, induced, initiated and/orenhanced inflammations are toxoplasmosis, acanthameba, toxocariasis,cysticercosis, onchocerciasis.

Examples of inflammatory diseases caused, induced, initiated and/orenhanced by fungi are histoplasmosis, coccidioidomycosis, candidiasis,aspergillosis, sporotrichosis, blastomycosis, and cryptococcosis.

Masquerade syndromes are, for instance, leukemia, lymphoma, retinitispigmentosa, and retinoblastoma.

Suspected immune-mediated diseases can be selected from the groupcomprising ankylosing spondylitis, Behcet's disease, Crohn's disease,drug or hypersensitivity reaction, interstitial nephritis, juvenilerheumatoid arthritis, Kawasaki's disease, multiple sclerosis, psoriaticarthritis, Reiter's syndrome, relapsing polychondritis, sarcoidosis,Sjogren's syndrome, systemic lupus erythematosus, ulcerative colitis,vasculitis, vitiligo, Vogt Koyanagi Harada syndrome.

Syndromes confined primarily to the eye are, for instance, acutemultifocal placoid pigmentary epitheliopathy, acute retinal necrosis,birdshot choroidopathy, Fuch's heterochromic cyclitis,glaucomatocyclitic crisis, lens-induced uveitis, multifocal choroiditis,pars planitis, serpiginous choroiditis, sympathetic ophthalmia, andtrauma.

Examples for inflammatory diseases of the larynx are gastroesophageal(laryngopharyngeal) reflux disease, pediatric laryngitis, acutelaryngeal infections of adults, chronic (granulomatous) diseases,allergic, immune, and idiopathic disorders and miscellaneousinflammatory conditions.

Pediatric laryngitis is known as acute (viral or bacterial) infectionsuch as laryngotracheitis (croup), supraglottitis (epiglottitis),diphtheria, and noninfectious causes are for example spasmodic croup andtraumatic laryngitis.

Acute laryngeal infections of adults are, for instance, virallaryngitis, common upper respiratory infection, laryngotracheitis,herpes simplex, bacterial laryngitis, supraglottitis, laryngeal abscess,and gonorrhea.

Chronic (granulomatous) diseases can be selected from the groupcomprising bacterial diseases, tuberculosis, leprosy, scleroma,actinomycosis, tularemia, glanders, spirochetal (syphilis) diseases,mycotic (fungal) diseases, candidiasis, blastomycosis, histoplasmosis,coccidiomycosis, aspergillosis, idiopathic diseases, sarcoidosis, andWegener's granulomatosis.

Allergic, immune, and idiopathic disorders are, for example,hypersensitivity reactions, angioedema, Stevens-Johnson syndrome, immuneand idiopathic disorders, infections of the immunocompromised host,rheuatoid arthritis, systeic lupus erythematosus, cicatricialpemphigoid, relapsing polychondritis, Sjogren's syndrome, andamyloidosis.

Miscellaneous inflammatory conditions are, for instance, parasiticinfections, trichinosis, leishmaniasis, schistosomiasis, syngamuslaryngeus, inhalation laryngitis, acute (thermal) injury, pollution andinhalant allergy, carcinogens, radiation injury, radiation laryngitis,radionecrosis, vocal abuse, vocal-cord hemorrhage, muscle tensiondysphonias, and contact ulcer and granuloma.

Stroke

The inventive compounds according to the general formula (I) as well aspharmaceutically acceptable salts thereof are also useful for treatmentof stroke.

In another aspect of the present invention, the compounds according tothe general formula (I) as well as pharmaceutically acceptable saltsthereof are used as an inhibitor for a protein kinase, preferably as aninhibitor for a cellular protein kinase.

In a preferred embodiment of this aspect said cellular protein kinaseconsists of Cyclin-dependent protein kinases (CDKs).

The cyclin-dependent protein kinase can be selected from the groupcomprising: CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10,CDK11, CrkRS (Crk7, CDC2-related protein kinase 7), CDKL1(cyclin-dependent kinase-like 1); KKIALRE, CDKL2 (cyclin-dependentkinase-like 2), KKIAMRE, CDKL3 (cyclin-dependent kinase-like 3),NKIAMRE, CDKL4, similar to cyclin-dependent kinase-like 1, CDC2L1 (celldivision cycle 2-like 1), PITSLRE B, CDC2L1 (cell division cycle 2-like1), PITSLRE A, CDC2L5 (cell division cycle 2-like 5), PCTK1 (PCTAIREprotein kinase 1), PCTK2 (PCTAIRE protein kinase 2), PCTK3 (PCTAIREprotein kinase 3) or PFTK1 (PFTAIRE protein kinase 1).

In a further preferred embodiment said cyclin-dependent protein kinaseis CDK9. Thus, the compounds according to the general formula (I) aswell as pharmaceutically acceptable salts thereof are used as aninhibitor for CDK9.

Surprisingly it turned out that the compounds according to the generalformula (I) as well as pharmaceutically acceptable salts thereofselectively inhibit CDK9 in comparison to other protein kinases and incomparison to other cyclin-dependent protein kinases. Thus, thecompounds according to the general formula (I) as well aspharmaceutically acceptable salts thereof are used as selectiveinhibitors for CDK9.

As used herein, a kinase “inhibitor” refers to any compound capable ofdownregulating, decreasing, suppressing or otherwise regulating theamount and/or activity of a kinase. Inhibition of these kinases can beachieved by any of a variety of mechanisms known in the art, including,but not limited to binding directly to the kinase polypeptide,denaturing or otherwise inactivating the kinase, or inhibiting theexpression of the gene (e.g., transcription to mRNA, translation to anascent polypeptide, and/or final polypeptide modifications to a matureprotein), which encodes the kinase. Generally, kinase inhibitors may beproteins, polypeptides, nucleic acids, small molecules, or otherchemical moieties.

As used herein the term “inhibiting” or “inhibition” refers to theability of a compound to downregulate, decrease, reduce, suppress,inactivate, or inhibit at least partially the activity of an enzyme, orthe expression of an enzyme or protein and/or the virus replication.

In a further aspect of the present invention, a method for preventingand/or treating infectious diseases, including opportunistic diseases,in a mammal, especially in a human, is provided, which method comprisesadministering to the mammal an amount of at least one compound accordingto the general formula (I), effective to prevent and/or treat saidinfectious diseases, including opportunistic diseases. In a preferredembodiment of this method, the infectious diseases, includingopportunistic diseases, are virally induced infectious diseases. Thevirally induced infectious diseases, including opportunistic diseases,are caused by retroviruses, hepadnaviruses, herpesviruses, flaviviridae,and/or adenoviruses. In a further preferred embodiment of this method,the retroviruses are selected from lentiviruses or oncoretroviruses,wherein the lentivirus is selected from the group comprising: HIV-1,HIV-2, FIV, BIV, SIVs, SHIV, CAEV, VMV or EIAV, preferably HIV-1 orHIV-2 and wherein the oncoretrovirus is selected from the groupconsisting of: HTLV-I, HTLV-II or BLV. In a further preferred embodimentof this method, the hepadnavirus is selected from HBV, GSHV or WHV,preferably HBV, the herpesivirus is selected from the group comprising:HSV I, HSV II, EBV, VZV, HCMV or HHV 8, preferably HCMV and theflaviviridae is selected from HCV, West nile or Yellow Fever.

In a further aspect of the present invention, methods for preventingand/or treating infectious diseases including opportunistic diseases,prion diseases, immunological diseases, autoimmune diseases,cardiovascular diseases, cell proliferative diseases, inflammation,erectile dysfunction and stroke in a mammal, especially in a human, areprovided, which methods comprise administering to the mammal an amountof at least one compound according to the general formula (I) and/orpharmaceutically acceptable salts thereof, effective to prevent and/ortreat said infectious diseases including opportunistic diseases, priondiseases, immunological diseases, autoimmune diseases, cardiovasculardiseases, cell proliferative diseases, inflammation, erectiledysfunction and stroke.

In further preferred embodiments, the specific diseases addressed asinfectious diseases including opportunistic diseases, prion diseases,immunological diseases, autoimmune diseases, cardiovascular diseases,cell proliferative diseases, inflammation, erectile dysfunction andstroke are selected from the groups disclosed above.

The compounds shown explicitly in Table 1 are preferred to be usedwithin the methods or indications disclosed herein. Another aspect ofthe present invention is that at least one compound according to thegeneral formula (I) used as a pharmaceutically active agent may beadministered in combination with further therapeutic compounds.

For the indication HIV compounds according to the general formula (I),preferably those falling under the activity range “a” for CDK9 as shownin Table 5, may be administered in combination with anti-retroviraldrugs, selected from the following five classes:

-   -   1) Nucleoside reverse transcriptase inhibitors (NRTIs),    -   2) Non-nucleoside reverse transcriptase inhibitors (NNRTIs),    -   3) Protease inhibitors (PIs),    -   4) Fusion inhibitors or    -   5) Immune stimuli.

Thus, another aspect of the present invention relates to drugcombinations comprising at least one inventive compound according togeneral formula (I) and/or pharmaceutically acceptable salts thereoftogether with at least one anti-retroviral drug, especially at least oneof the drugs mentioned above.

The pharmaceutical compositions according to the present inventioncomprise at least one compound according to the present invention as anactive ingredient together with at least one pharmaceutically acceptable(i.e. non-toxic) carrier, excipient and/or diluent. The pharmaceuticalcompositions of the present invention can be prepared in a conventionalsolid or liquid carrier or diluent and a conventionalpharmaceutically-made adjuvant at suitable dosage level in a known way.The preferred preparations are adapted for oral application. Theseadministration forms include, for example, pills, tablets, film tablets,coated tablets, capsules, powders and deposits.

Furthermore, the present invention also includes pharmaceuticalpreparations for parenteral application, including dermal, intradermal,intragastral, intracutan, intravasal, intravenous, intramuscular,intraperitoneal, intranasal, intravaginal, intrabuccal, percutan,rectal, subcutaneous, sublingual, topical, or transdermal application,which preparations in addition to typical vehicles and/or diluentscontain at least one compound according to the present invention and/ora pharmaceutical acceptable salt thereof as active ingredient.

The pharmaceutical compositions according to the present inventioncontaining at least one compound according to the present inventionand/or a pharmaceutical acceptable salt thereof as active ingredientwill typically be administered together with suitable carrier materialsselected with respect to the intended form of administration, i.e. fororal administration in the form of tablets, capsules (either solidfilled, semi-solid filled or liquid filled), powders for constitution,gels, elixirs, dispersable granules, syrups, suspensions, and the like,and consistent with conventional pharmaceutical practices. For example,for oral administration in the form of tablets or capsules, the activedrug component may be combined with any oral non-toxic pharmaceuticallyacceptable carrier, preferably with an inert carrier like lactose,starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate,calcium sulfate, talc, mannitol, ethyl alcohol (liquid filled capsules)and the like. Moreover, suitable binders, lubricants, disintegratingagents and coloring agents may also be incorporated into the tablet orcapsule.

Powders and tablets may contain about 5 to about 95-weight % of the4,6-disubstituted pyrimdine derivative according to the general formula(I) or analogues compound thereof or the respective pharmaceuticallyactive salt as active ingredient.

Suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol and waxes. Among suitablelubricants there may be mentioned boric acid, sodium benzoate, sodiumacetate, sodium chloride, and the like. Suitable disintegrants includestarch, methylcellulose, guar gum, and the like. Sweetening andflavoring agents as well as preservatives may also be included, whereappropriate. The disintegrants, diluents, lubricants, binders etc. arediscussed in more detail below.

Moreover, the pharmaceutical compositions of the present invention maybe formulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimise the therapeutic effect(s), e.g. antihistaminic activity and thelike. Suitable dosage forms for sustained release include tablets havinglayers of varying disintegration rates or controlled release polymericmatrices impregnated with the active components and shaped in tabletform or capsules containing such impregnated or encapsulated porouspolymeric matrices.

Liquid form preparations include solutions, suspensions, and emulsions.As an example, there may be mentioned water or water/propylene glycolsolutions for parenteral injections or addition of sweeteners andopacifiers for oral solutions, suspensions, and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be present in combination with apharmaceutically acceptable carrier such as an inert, compressed gas,e.g. nitrogen.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides like cocoa butter is melted first, and the activeingredient is then dispersed homogeneously therein e.g. by stirring. Themolten, homogeneous mixture is then poured into conveniently sizedmoulds, allowed to cool, and thereby solidified.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions, and emulsions.

The compounds according to the present invention may also be deliveredtransdermally. The transdermal compositions may have the form of acream, a lotion, an aerosol and/or an emulsion and may be included in atransdermal patch of the matrix or reservoir type as is known in the artfor this purpose.

The term capsule as recited herein refers to a specific container orenclosure made e.g. of methylcellulose, polyvinyl alcohols, or denaturedgelatins or starch for holding or containing compositions comprising theactive ingredient(s). Capsules with hard shells are typically made ofblended of relatively high gel strength gelatins from bones or porkskin. The capsule itself may contain small amounts of dyes, opaquingagents, plasticisers and/or preservatives.

Under tablet a compressed or moulded solid dosage form is understoodwhich comprises the active ingredients with suitable diluents. Thetablet may be prepared by compression of mixtures or granulationsobtained by wet granulation, dry granulation, or by compaction wellknown to a person of ordinary skill in the art.

Oral gels refer to the active ingredients dispersed or solubilised in ahydrophilic semi-solid matrix.

Powders for constitution refers to powder blends containing the activeingredients and suitable diluents which can be suspended e.g. in wateror in juice.

Suitable diluents are substances that usually make up the major portionof the composition or dosage form. Suitable diluents include sugars suchas lactose, sucrose, mannitol, and sorbitol, starches derived fromwheat, corn rice, and potato, and celluloses such as microcrystallinecellulose. The amount of diluent in the composition can range from about5 to about 95% by weight of the total composition, preferably from about25 to about 75 weight %, and more preferably from about 30 to about 60weight %.

The term disintegrants refers to materials added to the composition tosupport break apart (disintegrate) and release the pharmaceuticallyactive ingredients of a medicament. Suitable disintegrants includestarches, “cold water soluble” modified starches such as sodiumcarboxymethyl starch, natural and synthetic gums such as locust bean,karaya, guar, tragacanth and agar, cellulose derivatives such asmethylcellulose and sodium carboxymethylcellulose, microcrystallinecelluloses, and cross-linked microcrystalline celluloses such as sodiumcroscaramellose, alginates such as alginic acid and sodium alginate,clays such as bentonites, and effervescent mixtures. The amount ofdisintegrant in the composition may range from about 2 to about 20weight % of the composition, more preferably from about 5 to about 10weight %.

Binders are substances which bind or “glue” together powder particlesand make them cohesive by forming granules, thus serving as the“adhesive” in the formulation. Binders add cohesive strength alreadyavailable in the diluent or bulking agent. Suitable binders includesugars such as sucrose, starches derived from wheat corn rice andpotato, natural gums such as acacia, gelatin and tragacanth, derivativesof seaweed such as alginic acid, sodium alginate and ammonium calciumalginate, cellulose materials such as methylcellulose, sodiumcarboxymethylcellulose and hydroxypropylmethylcellulose,polyvinylpyrrolidone, and inorganic compounds such as magnesium aluminumsilicate. The amount of binder in the composition may range from about 2to about 20 weight % of the composition, preferably from about 3 toabout 10 weight %, and more preferably from about 3 to about 6 weight %.

Lubricants refer to a class of substances which are added to the dosageform to enable the tablet granules etc. after being compressed torelease from the mould or die by reducing friction or wear. Suitablelubricants include metallic stearates such as magnesium stearate,calcium stearate, or potassium stearate, stearic acid, high meltingpoint waxes, and other water soluble lubricants such as sodium chloride,sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols andD,L-leucine. Lubricants are usually added at the very last step beforecompression, since they must be present at the surface of the granules.The amount of lubricant in the composition may range from about 0.2 toabout 5 weight % of the composition, preferably from about 0.5 to about2 weight %, and more preferably from about 0.3 to about 1.5 weight % ofthe composition.

Glidents are materials that prevent caking of the components of thepharmaceutical composition and improve the flow characteristics ofgranulate so that flow is smooth and uniform. Suitable glidents includesilicon dioxide and talc. The amount of glident in the composition mayrange from about 0.1 to about 5 weight % of the final composition,preferably from about 0.5 to about 2 weight %.

Coloring agents are excipients that provide coloration to thecomposition or the dosage form. Such excipients can include food gradedyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.The amount of the coloring agent may vary from about 0.1 to about 5weight % of the composition, preferably from about 0.1 to about 1 weight%.

EXAMPLES Preparation of Compounds Abbreviations Used in the Descriptionof the Chemistry and in the Examples that Follow are

ACN (acetonitrile); CDCl₃ (deuterated chloroform); cHex (cyclohexane);DCM (dichloromethane); DIPEA (di-iso-propylethylamine); DME(1,2-dimethoxyethane); DMF (dimethylformamide); DMSO (dimethylsulfoxide); eq (equivalent); ES (electrospray); EtOAc (ethyl acetate);EtOH (ethanol); MeOH (methanol); MS (mass spectrometry); NMR (nuclearmagnetic resonance); Pd(dppf)Cl₂([1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) complexwith dichloromethane); Pd(PPh₃)₂Cl₂ (dichlorobis(triphenylphosphine)palladium(II)); iPrOH (iso-propanol); RT (room temperature); sat. aq.(saturated aqueous); SiO₂ (silica gel); TFA (trifluoroacetic acid); THF(tetrahydrofuran).

Preparative Examples Intermediates Intermediate 1:2-Chloro-4-(2-methoxyphenyl)pyridine (A1)

Method A:

To a solution of 4-bromo-2-chloro-pyridine (1.0 g, 5.2 mmol) inDME/water 10:1 (15 mL) was added (2-methoxyphenyl)boronic acid (0.79 g,5.2 mmol), Pd(PPh₃)₂Cl₂ (240 mg, 0.34 mmol), and K₂CO₃ (1.8 g, 13.0mmol). The mixture was heated with reflux for 6 hours. It was dilutedwith DCM, washed three times with water, dried over MgSO₄, andconcentrated under reduced pressure. The residue was purified by flashchromatography (silica gel, DCM/MeOH 100:0 to 90:10) to give the titlecompound A1 (0.6 g, 52%). MS (ES) C₁₂H₁₀ClNO requires: 219. found: 220(M+H)⁺.

Method B:

To a solution of 4-bromo-2-chloro-pyridine (1.5 g, 7.8 mmol) inDME/water/EtOH 5:1:1 (20 mL) was added (2-methoxyphenyl)boronic acid(1.49 g, 9.8 mmol), Pd(PPh₃)₂Cl₂ (112 mg, 0.16 mmol), and Na₂CO₃ (1.65g, 15.6 mmol). The mixture was heated at 125° C. for 90 minutes in amicrowave oven. It was concentrated under reduced pressure, and theresidue was purified by flash chromatography (silica gel, cHex/EtOAc100:0 to 80:20) to give the title compound A1 (1.07 g, 62%). MS (ES)C₁₂H₁₀ClNO requires: 219. found: 220 (M+H)⁺.

Intermediate 2: 2-Chloro-4-(4-fluoro-2-methoxyphenyl)pyridine (A2)

A mixture of 4-bromo-2-chloropyridine (1.92 g, 10 mmol),(4-fluoro-2-methoxyphenyl)boronic acid (1.70 g, 10 mmol) and K₃PO₄ (4.24g, 20 mmol) in dioxane/water 10:1 (20 mL) was degassed with a stream ofnitrogen for 10 min. After addition of Pd(dppf)Cl₂ (816 mg, 1 mmol) thereaction mixture was heated at 145° C. for 90 minutes in a microwaveoven. It was diluted with EtOAc and washed twice with sat. aq. NaHCO₃solution and once with brine. The organic layer was dried over MgSO₄ andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel (cHex/EtOAc 100:0 to 60:40) to yield thedesired product A2 as a white solid (1.07 g, 45%). ¹H NMR (400 MHz,d₆-DMSO, 300K) δ 3.81 (s, 3H), 6.87 (dt, J=8.5 Hz, J=3.5 Hz, 1H), 7.05(dd, J=11.4 Hz, J=2.5 Hz, 1H), 7.44 (dd, J=8.5 Hz, J=6.8 Hz, 1H), 7.48(dd, J=5.3 Hz, J=1.5 Hz, 1H), 7.55 (m, 1H), 8.38 (d, J=5.3 Hz, 1H). MS(ES) C₁₂H₉ClFNO requires: 237. found: 238 (M+H)⁺.

Intermediate 3: 2-Fluoro-4-(2-methoxyphenyl)pyridine (A3)

To a solution of 2-fluoro-4-iodo-pyridine (0.5 g, 2.24 mmol) and(2-methoxyphenyl)boronic acid (0.34 g, 2.24 mmol) in DME/water 2:1 (15mL) was added Pd(PPh₃)₂Cl₂ (20 mg, 0.028 mmol) and K₂CO₃ (20 mg, 0.15mmol). The mixture was heated at 80° C. for 6 hours. It was diluted withDCM, washed with water, dried over MgSO₄, and concentrated under reducedpressure. The residue was purified by flash chromatography (silica gel,DCM/MeOH 100:0 to 90:10) to give the title compound A3 (0.25 g, 55%). MS(ES) C₁₂H₁₀FNO requires: 203. found: 204 (M+H)⁺.

Intermediate 4: 4-((4-Iodopyridin-2-yl)amino)benzenesulfonamide (A4)

A mixture of 2-fluoro-4-iodopyridine (1.0 g, 4.48 mmol) and4-aminobenzenesulfonamide (772 mg, 4.48 mmol) was heated with an oilbath for 3 hours at 150° C. The title compound A4 was obtained from theresidue by preparative HPLC (water/ACN gradient). Yield: 135 mg (8%). MS(ES) C₁₁H₁₀IN₃O₂S requires: 375. found: 376 (M+H)⁺.

Intermediate 5: 4-Iodo-N-(3-nitrophenyl)pyridine-2-amine (A5)

A mixture of 2-fluoro-4-iodopyridine (500 mg, 2.24 mmol), 3-nitroaniline(620 mg, 4.49 mmol), and Cs₂CO₃ (1460 mg, 4.48 mmol) in dry DMF (12.5mL) was heated for 1 h at 130° C. in a microwave oven. The mixture wasdiluted with EtOAc and washed twice with brine. The organic layer wasdried over MgSO₄ and concentrated under reduced pressure, and theresidue was purified by flash chromatography on silica gel (DCM/MeOH100:0 to 95:5) to yield the desired product A5 as a white solid (122 mg,16%). ¹H NMR (400 MHz, d₆-DMSO, 300K) δ 7.21 (d, J=5.4 Hz, 1H), 7.29 (s,1H), 7.52 (t, J=8.1 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.93 (m, 2H), 8.74(t, J=2.1 Hz, 1H), 9.62 (s, 1H). MS (ES) C₁₁H₈IN₃O₂ requires: 341.found: 342 (M+H)⁺.

Intermediate 6: 2-(3-Aminophenyl)ethanesulfonamide (A6)

The compound A6 has been obtained by reduction of2-(3-nitrophenyl)-ethanesulfonamide according to the procedure describedin WO2009/076140, and the nitro compound from 2-(3-nitrophenyl)ethanolaccording to J. Med. Chem. 45 (2002), 567-583.

Example Compounds Example 1 4-(2-Methoxyphenyl)-N-phenylpyridin-2-amine(B1)

A mixture of A3 (80 mg, 0.39 mmol) and aniline (102 mg, 1.1 mmol) washeated for 20 minutes at 150° C. in a microwave oven. The title compoundB1 was obtained from the residue by preparative HPLC (water/ACNgradient) as an amorphous solid (20 mg, 19%). MS (ES) C₁₈H₁₆N₂Orequires: 276. found: 277 (M+H)⁺.

Example 2 4-(2-Methoxyphenyl)-N-(3-nitrophenyl)pyridin-2-amine (C1)

A mixture of A1 (200 mg, 0.91 mmol) and 3-nitroaniline (126 mg, 0.91mmol) was heated with an oil bath for 2 hours at 150° C. After additionof water and MeOH the precipitate of the title compound C1 was collectedby filtration, washed with MeOH, and dried in vacuo. Yield: 10 mg(3.4%). MS (ES) C₁₈H₁₅N₃O₃ requires: 321. found: 322 (M+H)⁺.

Example 3 4-(4-Fluoro-2-methoxyphenyl)-N-(3-nitrophenyl)pyridin-2-amine(C2)

The title compound C2 was prepared from A5 (122 mg, 0.36 mmol) and(4-fluoro-2-methoxyphenyl)boronic acid (112 mg, 0.66 mmol) following theprocedure reported for the intermediate A2. The residue was purified byflash chromatography on silica gel (cHex/EtOAc 100:0 to 50:50) to yieldthe desired product C2 as an orange solid (98 mg, 80%). MS (ES)C₁₈H₁₄FN₃O₃ requires: 339. found: 340 (M+H)⁺.

Example 4 3-[(4-(2-Methoxyphenyl)pyridin-2-yl)amino]benzenesulfonamide(D1)

A mixture of A1 (230 mg, 1.05 mmol) and 3-aminobenzenesulfonamide (180mg, 1.05 mmol) was heated with an oil bath for 3 hours at 150° C. Afteraddition of water and MeOH the precipitate of the title compound D1 wascollected by filtration, washed with MeOH, and dried in vacuo. Yield:147.6 mg (40%); colorless amorphous solid. ¹H NMR (400 MHz, d₆-DMSO,300K) δ 3.81 (s, 3H), 7.03-7.10 (m, 2H), 7.14-7.19 (m, 2H), 7.32-7.37(m, 2H), 7.37-7.42 (m, 1H), 7.42-7.49 (m, 2H), 7.49-7.58 (m, 1H), 7.82(bd, J=7.6 Hz, 1H), 8.06 (bs, 1H), 8.15 (d, J=5.8 Hz, 1H), 9.96 (bs,1H). MS (ES) C₁₈H₁₇N₃O₃S requires: 355. found: 356 (M+H)⁺.

Example 5N-(tert-Butyl)-3-[(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino]-benzenesulfonamide(D2)

A mixture of 2-fluoro-4-iodopyridine (100 mg, 0.45 mmol),3-amino-N-(tert-butyl)benzenesulfonamide (153 mg, 0.67 mmol), and Cs₂CO₃(291 mg, 0.89 mmol) in dry DMF (3 mL) was heated at 150° C. for 1.5 h ina microwave oven. After addition of (4-fluoro-2-methoxyphenyl)boronicacid (152 mg, 0.89 mmol) the mixture was degassed with a stream ofnitrogen for 5 minutes. Pd(dppf)Cl₂ (73 mg, 0.09 mmol) was added and thereaction mixture was heated to 140° C. for 90 minutes in a microwaveoven. The mixture was diluted with EtOAc and washed twice with sat. aq.NaHCO₃-solution and once with brine. The organic layer was dried overMgSO₄ and concentrated under reduced pressure, and the residue waspurified by preparative HPLC (water/ACN 95:5 to 0:100) to yield thedesired product D2 as a yellow solid (9 mg, 5%). ¹H NMR (400 MHz,d₆-DMSO, 300K) δ 1.12 (s, 9H), 3.82 (s, 3H), 6.89 (m, 2H), 6.97 (s, 1H),7.06 (dd, J=11.5 Hz, J=2.4 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.39 (m,2H), 7.44 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 8.18 (d, J=5.4 Hz, 1H), 8.24(m, 1H), 9.39 (s, 1H). MS (ES) C₂₂H₂₄FN₃O₃S requires: 429. found: 430(M+H)⁺.

Example 6 4-[(4-(2-Methoxyphenyl)pyridin-2-yl)amino]benzenesulfonamide(E1)

Method A:

A mixture of A1 (230 mg, 1.05 mmol) and 4-aminobenzenesulfonamide (180mg, 1.05 mmol) was heated with an oil bath for 1 hour at 150° C. Thetitle compound E1 was obtained from the residue by preparative HPLC(water (0.1% TFA)/MeOH (0.1% TFA) gradient) as a colorless amorphoussolid (82.5 mg, 22%). MS (ES) C₁₈H₁₇N₃O₃S requires: 355. found: 356(M+H)⁺.

Method B:

To a solution of A4 (135 g, 0.36 mmol) in DME/water 9:1 (10 mL) wasadded (2-methoxyphenyl)boronic acid (55 mg, 0.36 mmol), Pd(PPh₃)₂Cl₂ (10mg, 0.014 mmol), and K₂CO₃ (100 mg, 0.72 mmol). The mixture was heatedat 80° C. for 45 minutes in a microwave oven. It was concentrated underreduced pressure, and the residue was purified by preparative HPLC(water (0.1% TFA)/MeOH (0.1% TFA) gradient) to give the title compoundE1 (38.7 g, 30%). ¹H NMR (400 MHz, d₆-DMSO, 300K) δ 3.80 (s, 3H), 6.95(dd, J=5.3 Hz, J=1.5 Hz, 1H), 7.03-7.08 (m, 2H), 7.10 (bs, 2H), 7.15 (d,J=8.3 Hz, 1H), 7.35 (dd, J=7.6 Hz, J=1.7 Hz, 1H), 7.38-7.43 (m, 1H),7.69 (d, J=8.9 Hz, 2H), 7.84 (d, J=8.8 Hz, 2H), 8.22 (d, J=5.3 Hz, 1H),9.48 (s, 1H). MS (ES) C₁₈H₁₇N₃O₃S requires: 355. found: 356 (M+H)⁺.

Example 74-(2-Methoxyphenyl)-N-(3-(methylsulfonyl)phenyl)pyridin-2-amine (F1)

F1 was prepared from A1 (281 mg, 1.28 mmol) and3-(methylsulfonyl)aniline hydrochloride (267 mg, 1.28 mmol) followingthe procedure reported for C1. Yield: 210 mg (46%). ¹H NMR (400 MHz,d₆-DMSO, 300K) δ 3.18 (s, 3H), 3.80 (s, 3H), 7.02-7.08 (m, 2H),7.12-7.18 (m, 2H), 7.35-7.45 (m, 2H), 7.50-7.53 (m, 1H), 7.53-7.62 (m,1H), 7.92 (d, J=8.0 Hz, 1H), 8.12-8.19 (m, 2H), 10.05 (bs, 1H). MS (ES)C₁₉H₁₈N₂O₃S requires: 354. found: 355 (M+H)⁺.

Example 8[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]-methanesulfonamide(G1)

Intermediate A2 (119 mg, 0.5 mmol), (3-aminophenyl)methanesulfonamide(112 mg, 0.6 mmol), NaOC(CH₃)₃ (67 mg, 0.7 mmol), PdCl₂(CH₃CN)₂ (6.5 mg,0.025 mmol, 5 mol %), and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) [Xantphos] (23mg, 0.04 mmol, 8 mol %) were dissolved in dry DMF (4 mL) and purged for10 minutes with nitrogen. After heating at 110° C. for 18 hours thereaction mixture was filtered and the residue washed with toluene. Thefiltrate was concentrated under reduced pressure and purified byautomated column chromatography (ISCO, gradient MeOH/DCM). The collectedfractions which contained the title compound were further purified bypreparative HPLC to yield 24 mg (12%) of G1 as an off-white solid. ¹HNMR (300 MHz, d₆-DMSO, 298K) δ 3.84 (s, 3H), 4.22 (s, 2H), 6.81-6.94 (m,5H), 6.98 (s, 1H), 7.07 (dd, J=11.7 Hz, J=4.2 Hz, 1H), 7.26 (t, J=6.6Hz, 1H), 7.39 (dd, J=6.9 Hz, J=6.0 Hz, 1H), 7.56-7.61 (m, 1H), 7.79 (d,J=7.5 Hz, 1H), 8.16 (d, J=6.0 Hz, 1H), 9.12 (s, 1H).

MS (ES) C₁₉H₁₈FN₃O₃S requires: 387. found: 388 (M+H)⁺.

Example 9[3-((4-(2-Methoxyphenyl)pyridin-2-yl)amino)phenyl]-methanesulfonamide(G2)

G2 was prepared from (3-aminophenyl)methanesulfonamide (85 mg, 0.46mmol) and A1 (100 mg, 0.46 mmol) following the procedure reported for G1by heating in DMF for 3 hours, and it was obtained as a colorlessamorphous solid (3.1 mg, 2%). ¹H NMR (400 MHz, d₆-DMSO, 300K) δ 3.79 (s,3H), 4.15 (s, 2H), 6.73 (bs, 2H), 6.84 (dd, J=5.3 Hz, J=1.5 Hz, 1H),6.96-6.98 (m, 1H), 7.04 (dt, J=1.0 Hz, J=8.0 Hz, 1H), 7.13 (d, J=8.2 Hz,1H), 7.21-7.25 (m, 2H), 7.33 (dd, J=7.6 Hz, J=1.8 Hz, 1H), 7.36-7.42 (m,1H), 7.64-7.68 (m, 2H), 8.14 (d, J=5.3 Hz, 1H), 9.08 (s, 1H). MS (ES)C₁₉H₁₉N₃O₃S requires: 369. found: 370 (M+H)⁺.

Example 101-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]-N,N-dimethylmethanesulfonamide(G3)

The title compound G3 was prepared from1-(3-aminophenyl)-N,N-dimethylmethanesulfonamide (400 mg, 1.87 mmol) andintermediate A2 (532 mg, 2.24 mmol) following the procedure reported forG1 by heating the reaction mixture for 2 h at 140° C. in a microwaveoven. The desired product G3 was obtained by flash chromatography onsilica gel (cHex/EtOAc 80:20 to 20:80) as a white solid (274 mg, 35%).¹H NMR (400 MHz, d₆-DMSO, 300K) δ 2.71 (s, 6H), 3.81 (s, 3H), 4.34 (s,2H), 6.82 (dd, J=5.3 Hz, J=1.5 Hz, 1H), 6.88 (dt, J=8.3 Hz, J=1.5 Hz,1H), 6.91 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 7.05 (dd, J=11.4 Hz, J=2.4Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.38 (dd, J=8.3 Hz, J=7.0 Hz, 1H), 7.67(s, 1H), 7.72 (d, J=8.3 Hz, 1H), 8.14 (d, J=5.3 Hz, 1H), 9.11 (s, 1H).MS (ES) C₂₁H₂₂FN₃O₃S requires: 415. found: 416 (M+H)⁺.

Example 112-[3-((4-(2-Methoxyphenyl)pyridin-2-yl)amino)phenyl]-ethanesulfonamide(H1)

H1 was prepared from A6 (92 mg, 0.46 mmol) and A1 (100 mg, 0.46 mmol)following the procedure reported for G1 and obtained as a pale yellowamorphous solid (4 mg, 2%). ¹H NMR (400 MHz, d₆-DMSO, 300K) δ 2.95-3.03(m, 2H), 3.21-3.29 (m, 2H), 3.81 (s, 3H), 6.87 (bs, 2H), 6.93-7.01 (m,2H), 7.07 (t, J=7.5 Hz, 1H), 7.10-7.14 (m, 1H), 7.16 (d, J=8.5 Hz, 1H),7.29 (t, J=8.0 Hz, 1H), 7.36-7.47 (m, 4H), 8.07 (d, J=5.4 Hz, 1H), 9.67(bs, 1H). MS (ES) C₂₀H₂₁N₃O₃S requires: 383. found: 384 (M+H)⁺.

Example 12N¹-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)benzene-1,3-diamine (I1)

To a solution of C2 (98 mg, 0.29 mmol) in THF/MeOH 1:1 (20 mL) was addedPd/C (10% w/w, 46 mg). The reaction mixture was stirred under hydrogenatmosphere (1 atm) at RT for 15 hours. The suspension was filteredthrough a pad of Celite® and the solvent was removed in vacuo to leavethe desired product I1 as a brown solid (89 mg, 99%). MS (ES) C₁₈H₁₆FN₃Orequires: 309. found: 310 (M+H)⁺.

Example 13N-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]-methanesulfonamide(J1)

To a solution of I1 (44 mg, 0.14 mmol) in dry pyridine (1 mL) was addedmethanesulfonyl chloride (24 mg, 0.21 mmol). After 2 h stirring at RTMeOH (0.1 mL) was added and the solvents were removed in vacuo. Theresidue was purified by flash chromatography on silica gel (EtOAc/MeOH100:0 to 90:10) to yield the desired product J1 as a beige solid (36 mg,66%). ¹H NMR (400 MHz, d₆-DMSO, 300K) δ 3.01 (s, 3H), 3.82 (s, 3H), 6.91(t, J=7.7 Hz, 1H), 6.97 (d, J=7.0 Hz, 1H), 7.08 (m, 2H), 7.20-7.37 (m,4H), 7.47 (t, J=7.0 Hz, 1H), 8.04 (d, J=5.3 Hz, 1H), 9.86 (s, 1H), 10.23(bs, 1H).

MS (ES) C₁₉H₁₈FN₃O₃S requires: 387. found: 388 (M+H)⁺.

Example 14N-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]-acetamide(J2)

The title compound J2 was prepared from I1 (44 mg, 0.14 mmol) and acetylchloride (17 mg, 0.22 mmol) following the procedure described for J1 andobtained as a yellow solid (25 mg, 51%). ¹H NMR (400 MHz, d₆-DMSO, 300K)δ 2.03 (s, 3H), 3.82 (s, 3H), 6.90 (t, J=7.8 Hz, 1H), 7.01 (d, J=5.2 Hz,1H), 7.08 (d, J=11.1 Hz, 1H), 7.16-7.30 (m, 5H), 7.46 (t, J=7.3 Hz, 1H),7.80 (s, 1H), 8.05 (d, J=5.5 Hz, 1H), 10.06 (s, 1H). MS (ES) C₂₀H₁₈FN₃O₂requires: 351. found: 352 (M+H)⁺.

Example 151-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]-N-propylmethanesulfonamide(K1)

A mixture of G3 (60 mg, 0.14 mmol), Cs₂CO₃ (94 mg, 0.29 mmol) andpropylamine (0.2 mL, 2.43 mmol) in dioxane/water 10:1 (3.3 mL) washeated in a microwave oven for 8 h at 180° C. The mixture was purifiedby preparative HPLC (water/ACN 60:40 to 40:60) to yield the desiredproduct K1 as a white solid (20 mg, 33%). ¹H NMR (400 MHz, d₆-DMSO,300K) δ 0.81 (t, J=7.3 Hz, 3H), 1.41 (sext, J=7.3 Hz, 2H), 2.85 (t,J=7.3 Hz, 2H), 3.81 (s, 3H), 4.22 (s, 2H), 6.83 (dd, J=5.3 Hz, J=1.4 Hz,1H), 6.87 (m, 3H), 6.96 (s, 1H), 7.04 (dd, J=11.5 Hz, J=2.4 Hz, 1H),7.23 (t, J=7.8 Hz, 1H), 7.37 (dd, J=8.5 Hz, J=6.9 Hz, 1H), 7.61 (s, 1H),7.73 (dd, J=7.8 Hz, J=1.4 Hz, 1H), 8.13 (d, J=5.3 Hz, 1H), 9.09 (s, 1H).MS (ES) C₂₂H₂₄FN₃O₃S requires: 429. found: 430 (M+H)⁺.

Materials and Methods:

1. Measurement of Binding Affinities to CDKs

This protocol describes how the LanthaScreen Eu Kinase Binding Assay wasperformed to determine dissociation constants (K_(d)) of compounds ofgeneral formula (I) and CDK/Cyclin complexes. The principle behind thisassay is based upon the binding and displacement of an Alexa Fluor647-labeled tracer, which binds to the active site of kinases. Bindingof the tracer to the kinase is detected using a Eu-labeled antibody.Simultaneous binding of both the tracer and antibody to the kinase givesrise to a FRET-signal. Binding of an inhibitor to the kinase competesfor binding with the tracer, resulting in a loss of FRET.

TABLE 2 Reagents, stock concentrations and final assay concentrationsKinase- Tracer- Antibody- Kinase Supplier conc. [nM] Tracer Supplierconc.[nM] Antibody Supplier conc. CDK2/Cyclin A Proqinase  5 236Invitrogen 20 Eu-Anti-GST Cisbio 1:750 (135 kDa) CDK7/CyclinH/MAT1 Carna 5 236 Invitrogen 60 Eu-Anti-His Invitrogen 2 nM (126 kDa) BiosciencesCDK8/Cyclin C Invitrogen  5 236 lnvitrogen 20 Eu-Anti-His Invitrogen 2nM (97 kDa) CDK9/Cyclin T1 Invitrogen  5 236 Invitrogen 30 Eu-Anti-HisCisbio 1:250 (132 kDa CDK9/Cyclin K Invitrogen 10 236 Invitrogen 35Eu-Anti-His Invitrogen 4 nM (92 kDa)

The compounds of general formula (I) summarized in Table 1 were dilutedfrom a 10 mM DMSO stock solution 1:10 in a total volume of 15 μL DMSO.This compound predilution was then serial diluted 1:3 over 8 steps inDMSO and briefly spun down. Each compound solution was now diluted1:33.33 in kinase buffer (HEPES: 20 mM, pH: 8.0; MgCl₂: 10 mM; DTT: 1mM; Brij-35: 0.01%), mixed thoroughly and spun down. For every sample, 5μL of the diluted compound were mixed with 5 μL tracer working solution(e.g. 60 nM tracer 236 in kinase buffer for CDK2/Cyclin A) and 5 μLCDK/Cyclin/Anti-GST-AB-working solution (e.g. 15 nM CDK2/Cyclin A, 1:250dilution of Anti-GST-AB in kinase buffer) in a well of a small volume384 well plate (Corning Incorporated, Corning, N.Y., USA; order no.3673). The tracer concentration was adjusted to its dissociationconstant (K_(d)) for the CDK/Cyclin, which was 30 nM for CDK2/Cyclin A,CDK7/Cyclin H and CDK9/Cyclin T1, 20 nM for CDK8/Cyclin C, and 35 nM forCDK9/Cyclin K. For negative controls, in each well 5 μL of DMSO workingsolution (3% DMSO diluted in kinase buffer) was mixed with 5 μLAnti-GST-AB working solution (e.g. 1:250 dilution of Anti-GST-AB inkinase buffer for CDK2/Cyclin A) and 5 μL Tracer working solution (e.g.60 nM Tracer 236 in kinase buffer for CDK2/Cyclin A). For positivecontrols, in each well 5 μL of DMSO working solution (3% DMSO diluted inkinase buffer) was mixed with 5 μL CDK/Cyclin/Anti-GST-AB-workingsolution: (e.g. 15 nM CDK2/Cyclin A, 1:250 dilution of Anti-GST-AB inkinase buffer) and 5 μL Tracer working solution (e.g. 60 nM Tracer 236in kinase buffer for CDK2/Cyclin A). Positive and negative controls werecalculated from at least 8 different sample wells. The 384 well plateswere mixed in a Teleshaker plate mixer (Beckman Coulter, Brea, Calif.,USA) at 2000 rpm for 40 sec, and incubated for 1 h at room temperaturebefore reading. The FRET signal was measured at 340 nm excitation, 665nm and 615 nm emission (for the kinase tracer and LanthaScreen Eu-AB,respectively) with an Envision spectrophotometer (Perkin Elmer, Waltham,Mass., USA) with 50 μs delay and 300 μs integration time. K_(d) valueswere determined from the sigmoidal dose response curves with thesoftware Quattro Workflow (Quattro GmbH, Munich, Germany). Results arepresented in Table 4.

2. Measurement of Half Maximal Inhibitory Concentration to CDKs

This protocol describes how the Lance Ultra KinaSelect Assay wasperformed to determine half maximal inhibitory concentration (IC₅₀) ofcompounds of general formula (I) and CDK/Cyclin complexes. The principlebehind this enzymatic assay is based upon the phosphorylation of theULight-Peptide Substrat. It is detected by using a specific EU-labeledanti-phospho peptide antibody. The binding of the Eu-labeledanti-phospho peptide antibody to the phosphorylated ULight labeledpeptide gives rise to a FRET-signal. Binding of an inhibitor to thekinase prevents phosphorylation of the ULight-MBP Substrat, resulting ina loss of FRET.

TABLE 3 Reagents, stock concentrations and final assay concentrationsKinase- ATP- Substrat- Antibody Kinase Supplier conc. [nM] conc. [μM]Substrat Supplier conc. [nM] Antibody Supplier conc. [nM] CDK1/CyclinB1Carna  2 20 Ulight MBP Perkin Elmer 50 Eu-anti-P-MBP Perkin Elmer 0.25(91 kDa) CDK2/CyclinA Proqinase  5 3 Ulight MBP Perkin Elmer 50Eu-anti-P-MBP Perkin Elmer 0.25 (135 kDa) CDK4/CyclinD1 Invitrogen 10 90Ulight MBP Perkin Elmer 50 Eu-anti-P-MBP Perkin Elmer 0.25 (123 kDa)CDK6/CyclinD3 Carna  5 55 Ulight MBP Perkin Elmer 50 Eu-anti-P-MBPPerkin Elmer 0.025 (123 kDa) CDK7/CyclinH/ Invitrogen 10 25 Ulight MBPPerkin Elmer 50 Eu-anti-P-MBP Perkin Elmer 0.25 MAT1 (126 kDa)CDK9/CyclinT1 Invitrogen 10 25 Ulight MBP Perkin Elmer 50 Eu-anti-P-MBPPerkin Elmer 0.,25 (132 kDa) CDK9/CyclinK Invitrogen 10 125 Ulight MBPPerkin Elmer 50 Eu-anti-P-MBP Perkin Elmer 0.25 (92 kDa)

The compounds of general formula (I) summarized in Table 5 were dilutedfrom a 10 mM DMSO stock solution 1:10 in a total volume of 15 μL DMSO.This compound predilution was then serial diluted 1:3 over 8 steps inDMSO and briefly spun down. Each compound solution was now diluted 1:20in Enzymatic Buffer (HEPES: 50 mM, pH: 7.5; MgCl₂: 10 mM; EGTA: 1 mM;DTT: 2 mM; Tween-20: 0.01%), mixed thoroughly and spun down. For everysample, 2 μL of the diluted compound were mixed with 6 μLCDK/Cyclin/Substrat solution and 2 μL ATP solution in a well of a smallvolume 384 well plate (Corning Incorporated, Corning, N.Y., USA; orderno. 3673). The CDK/Cyclin was diluted to the appropriate concentration(see Table 3) and the ATP concentration was adjusted to its IC₅₀concentration for the CDK/Cyclin, which was 3 μM for CDK2/Cyclin A, 20μM for CDK1/Cyclin B1, 25 μM for CDK7/Cyclin H and CDK9/Cyclin T1, 55 μMfor CDK6/Cyclin D3, 90 μM for CDK4/Cyclin D1 and 125 μM for CDK9/CyclinK. For negative controls, in each well 2 μL of DMSO solution (1% finalDMSO assay concentration) was mixed with 6 μL substrate solution (50 nMULight MBP final assay concentration) and 2 μL ATP solution (appropriatefinal concentration see Table 3). For positive controls, in each well 2μL of DMSO solution (1% final DMSO assay concentration) was mixed with 6μL CDK/Cyclin/Substrat (appropriate final concentration see Table 3) and2 μL Tracer ATP solution (appropriate final concentration see Table 3).Positive and negative controls were calculated from at least 8 differentsample wells. The 384 well plates were mixed in a Teleshaker plate mixer(Beckman Coulter, Brea, Calif., USA) at 2000 rpm for 40 sec, andincubated for 1 h at room temperature. Before reading, 10 μL thedetection buffer (Lance Detection Buffer 1×; EDTA: 20 nM; Eu-Anti-P-MBP:see Table 3) was added. The FRET signal was measured at 340 nmexcitation, 665 nm and 615 nm emission (for the kinase tracer andLanthaScreen Eu-AB, respectively) with an Envision spectrophotometer(Perkin Elmer, Waltham, Mass., USA) with 50 μs delay and 300 μsintegration time. IC₅₀ values were determined from the sigmoidal doseresponse curves with the software Quattro Workflow (Quattro GmbH,Munich, Germany). Results are presented in Table 5.

3. Cellular Assays

3.1 RNA-Polymerase II Ser2 Cellular Phosphorylation Assay:

HCT-116 cells (DSMZ, Braunschweig, Germany) were maintained in Mc Coy'scell culture medium+glutamine (PAN Biotech GmbH, Aidenbach, Germany)supplemented with 10% fetal calf serum (PAA Laboratories GmbH, Pasching,Austria) and grown at 37° C., 5% CO₂. For the cellular phosphorylationassay, cells were seeded with 2×105 cells/well/1 ml in 24-well plates(Greiner Bio One, Frickenhausen, Germany; catalog #662160). Thecompounds of general formula (I) summarized in Table 6 were diluted froma 10 mM DMSO stock solution 1:10 in a total volume of 15 μL DMSO. Afterovernight incubation at 37° C./5% CO₂, 1.5 μL of a compound diluted inDMSO was added to each sample well. Wells with cells and 0.15% DMSO inculture medium were used as positive controls, wells without cells and0.15% DMSO in culture medium were used as negative controls. The cellswere incubated with the compounds for 72 h at 37° C./5% CO₂. Beforelysis, cells were washed with phosphate buffered saline. Phosphorylationof RNA Polymerase II Ser2 and tubulin levels for normalization wereanalyzed afterwards with the Multi-Array technology (Meso ScaleDiscovery, Gaithersburg, Md., USA), a combination of antibody coupledelectrochemiluminescence detection and patterned arrays. Manufacturer'sinstructions were followed and all solutions were purchased from MesoScale Discovery. In brief, cells were lysed by 30 min incubation in CLB1lysis buffer (Zeptosens, Witterswil, Switzerland; 60 μL per well), andsupernatants were cleared by centrifugation. For analysis of RNAPolymerase II Ser2-phosphorylation, lysates were diluted 1:50 with MesoScale Lysis Buffer supplemented with phosphatase- andprotease-inhibitors, and 25 μL of each sample was pipetted in a well ofa MSD Multi-Array 96-Well Plate Sector® Imager High Bind Plate (MesoScale Discovery; catalog #L15XB-3/L11XB-3), and incubated for 2 h atroom temperature. 150 μL Meso Scale Tris Wash Buffer supplemented with3% w/v Meso Scale Blocker A were added per well, then plates were sealedand incubated 1 h with vigorous shaking. Plates were washed with 1× TrisWash Buffer (10× Meso Scale Wash Buffer diluted 1:10 in destilledwater), 25 μL of antibody solution was added (CTD7 3E10 antibody fromHelmholtz Zentrum Munich, Germany, diluted 1:100 in Meso Scale Tris WashBuffer supplemented with 1% w/v Meso Scale Blocker A), and plates werewashed three times in 1× Tris Wash Buffer. 25 μL of MSD® SULFO-TAG™Goat-Anti-Rat-Antibody (Meso Scale Discovery, atalog # R32AH-1, diluted1:125 in Tris Wash Buffer with 1% (w/v) blocker A) were added per well,plates were sealed and incubated with vigorous shaking for 1 h at roomtemperature. Finally, plates were washed three times with Tris WashBuffer, 150 μl 2× Read Buffer (Meso Scale Discovery) were added per welland plates were analyzed immediately in a Sector Imager from Meso ScaleDiscovery. For determination of tubulin protein levels, samples wereanalyzed with the protocol for RNA Polymerase II Ser2-phosphorylation,with an anti-tubulin antibody (rabbit; BIODESIGN International, catalog#T59840R, diluted 1:100) and a MSD® SULFO-TAG™ Goat-Anti-Rat-Antibody(Meso Scale Discovery, catalog #R32AH-1, diluted 1:125). RNA PolymeraseII Ser2 phosphorylation was normalized with tubulin protein levels, andIC₅₀ values were calculated with the software XLFit (IDBS, Guildford,UK) from 2-fold dilution series comprising 6 concentrations induplicates. Results are presented in Table 6.

3.2 NF-kappaB Reporter Assay

Cells were maintained in RPMI cell culture medium+glutamine (PAN BiotechGmbH, Aidenbach, Germany) supplemented with 10% fetal calf serum (PAALaboratories GmbH, Pasching, Austria) and grown at 37° C., 5% CO₂.HEK293 cells grown to 50% confluence were transfected with the Amaxa®Cell Line Nucleofector® Kit V (Lonza, Basel, Switzerland, catalog #VCA-1003). Transfections were performed according to manufacturer'soptimized protocol for transfection of HEK293 cells. In brief, 2×10⁵cells were transfected with 5 μg highly purified plasmid DNA. Cells weretransfected with a NF-kappa B reporter plasmid (pNFkBluc), pTALluc forcontrol, or pMAXGFP for transfection control. After transfection, cellswere taken up in 500 μL RPMI1640 cell culture medium, incubated for 1 hat 37° C., and 4.5 ml DMEM without phenol red were added pertransfection. Transfected cells were seeded in 96 well plates (GreinerBio-One, Frickenhausen, Germany, catalog #655098) with 100 μL cellsuspension per well and incubated for 48 h. To each well, 100 μL DMEMwith 2× concentrated compound diluted from 10 mM DMSO stocks, or 100 μLDMEM with 0.4% DMSO for control wells, was added. The compounds ofgeneral formula (I) summarized in Table 6 were used in this assay. Cellswere stimulated with 20 ng/ml TNF alpha, and plates were incubated for 5h at 37° C./5% CO₂. Cell culture supernatants were removed to leave 100μl medium per well, followed by addition of 100 μl Bright Glo luciferaseassay reagent (Promega, Madison, Wis., USA, catalog # E2620), andshaking for 5 minutes in the dark. Luminescence was measured with aVictor Photospectrometer (Perkin Elmer, Waltham, Mass., USA). IC₅₀values were calculated with the software Excel Fit (IDBS, Guildford, UK)from 2-fold dilution series comprising at least 10 concentrations induplicates. Results are presented in Table 6.

3.3 TNF Alpha Release Assay

Freshly isolated peripheral blood mononuclear cells (PBMCs) were seededin 96-well cell culture plates with 200,000 cells in 100 μl cell culturemedium (DMEM cell culture medium+glutamine from PAN Biotech GmbH,Aidenbach, Germany) supplemented with 10% fetal calf serum (PAALaboratories GmbH, Pasching, Austria) per well and incubated overnightat 37° C., 5% CO₂. To each well, 100 μL cell culture medium with 2×concentrated test compounds diluted from 10 mM DMSO stocks, or 100 μLDMEM with 0.4% DMSO for control wells, was added. The compounds ofgeneral formula (I) summarized in Table 6 were used in this assay. Afterincubation for 1 h at 37° C., 5% CO₂, cells were stimulated with 1 μg/mLLPS (Lipopolysaccharides, Sigma, catalog #L4391-1 MG; 1 mg/ml stocksolution), or left untreated for negative controls, and plates wereincubated for 6 h at 37° C./5% CO₂. The cell culture plates werecentrifuged at 2000 rpm for 5 minutes, and supernatants were transferredto fresh 96-well polypropylene plates. 25 μL of supernatants weretransferred into 96-well-plates of the human TNF alpha-tissue culturekit (Meso Scale Discovery, Gaithersburg, Md., USA), and manufacturer'sinstructions were followed for analysis of TNF alpha levels.Chemoluminescence was measured in the Mesoscale Sector Imager, and IC₅₀values were calculated with the software Excel Fit (IDBS, Guildford, UK)from 2-fold dilution series comprising at least 6 concentrations induplicates. Results are presented in Table 6.

3.4 Cell Viability Assays

Hela- or MDAMB468-Cells were maintained in RPMI 1640 or McCoy's 5A cellculture medium+glutamine (PAN Biotech GmbH, Aidenbach, Germany; orderno. P04-22100; P04-05500) supplemented with 10% fetal calf serum “Gold”(PAA Laboratories GmbH, Pasching, Austria; order no. A15-151) and grownat 37° C., 5% CO₂. For the cell viability assay, cells were seeded witha density of 400 (Hela cells, DSMZ Braunschweig order no. ACC57) or 800(MDAMB468 cells, ATCC order no. HTB-132) per well in 25 μL in 384-wellplates (Greiner Bio-One, Frickenhausen, Germany; order no. 781080).After overnight incubation at 37° C./5% CO₂, 25 nL or 75 nL compoundwere added to each sample well by using BIOMEK FXP Laboratory AutomationWorkstation (Beckman Coulter, USA). Wells with cells and 0.1% or 0.3%DMSO in culture medium were used as positive controls, wells with cellsand 10 μM staurosporine in culture medium were used as negativecontrols. The cells were incubated with the compounds for 72 h at 37°C./5% CO₂. For measurement of cell viability 25 μL Cell Titer Gloreagent (Promega, Madison, USA; order no. G7573), 1:2 diluted with cellculture medium, was added to each well. The 384 well-plates were placedfor 2 min on a orbital microplate shaker and incubated for further 10min at room temperature to stabilize the luminescence signal.Luminescence was measured by Envision Plate Reader (Perkin Elmer, USA).IC₅₀ values were calculated with the software Excel Fit (IDBS,Guildford, UK) from 3-fold dilution series comprising at least 8concentrations in duplicates. Results are presented in Table 6.

Results:

1. Measurement of Binding Affinities to CDKs

The dissociation constants K_(d) of the compounds according to thepresent invention for binding to CDK9, CDK7, and CDK2, respectively, aresummarized in Table 4. Comparison of binding constants of a specialcompound of formula (I) for a number of different CDKs shows thatbinding of a compound to CKD9 is always stronger than binding to otherCDKs. Thus, a compound of formula (I) binds or interacts specificallywith CKD9 and at least selectively with CDK9.

TABLE 4 Affinity for CDK9, CDK7, and CDK2 of compounds according to thepresent invention {circle around (1)} Nomenclature {circle around (2)}{circle around (3)} {circle around (4)} {circle around (5)} B14-(2-Methoxyphenyl)-N-phenylpyridin-2-amine c n.t. n.t. n.t. C14-(2-Methoxyphenyl)-N-(3-nitrophenyl)pyridin-2-amine b b n.t. n.t. D13-[(4-(2-Methoxyphenyl)pyridin-2-yl)amino]benzenesulfonamide a a d a D2N-(tert-Butyl)-3-[(4-(4-fluoro-2-methoxyphenyl)pyridin-2-yl)amino]benzenesulfonamidec n.t. d n.t. E14-[(4-(2-Methoxyphenyl)pyridin-2-yl)amino]benzenesulfonamide b a d a F14-(2-Methoxyphenyl)-N-(3-(methylsulfonyl)phenyl)pyridin-2-amine a a n.t.b G1[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]methanesulfonamidea a d b G2[3-((4-(2-Methoxyphenyl)pyridin-2-yl)amino)phenyl]methanesulfonamide an.t. d a G31-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]-N,N- an.t. d b dimethylmethanesulfonamide H12-[3-((4-(2-Methoxyphenyl)pyridin-2-yl)amino)phenyl]ethanesulfonamide an.t. d b J1N-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]methanesulfonamidea n.t. c a J2N-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]acetamide an.t. d b K11-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]-N- a n.t.d b propylmethanesulfonamide Activity range “a” means, that thecompounds do have a K_(d) (dissociation constant) <100 nM, activityrange “b” means, that the compounds do have a K_(d) between 100 and 1000nM, activity range “c” means that the compounds do have an K_(d) between1000 and 10000 nM, activity range “d” means that the compounds do havean K_(d) > 10000 nM; “n.t.” means that the compounds have not beentested in this assay. {circle around (1)} Compound Number {circle around(2)} CDK9/Cyclin T1 (activity range) {circle around (3)} CDK9/Cyclin K(activity range) {circle around (4)} CDK7 (activity range) {circlearound (5)} CDK2 (activity range)2. Measurement of Half Maximal Inhibitory Concentration to CDKs inEnzymatic Assays

The inhibitory activities of the compounds according to the presentinvention are shown in Table 5 as half-maximal inhibition constant(IC₅₀) values for inhibition of CDK9, CDK1, CDK2, CDK4, CDK6, and CDK7,respectively.

TABLE 5 Inhibition for CDK9, CDK1, CDK2, CDK4, CDK6, and CDK7 ofcompounds according to the present invention {circle around (1)}Nomenclature {circle around (2)} {circle around (3)} {circle around (4)}{circle around (5)} {circle around (6)} {circle around (7)} B14-(2-Methoxyphenyl)-N-phenylpyridin-2-amine c n.t. n.t. n.t. n.t. n.t.C1 4-(2-Methoxyphenyl)-N-(3-nitrophenyl)pyridin-2-amine c n.t. n.t. n.t.n.t. n.t. D1 3-[(4-(2-Methoxyphenyl)pyridin-2-yl)amino] a c b d d dbenzenesulfonamide E1 4-[(4-(2-Methoxyphenyl)pyridin-2-yl)amino] b n.t.a n.t. n.t. d benzenesulfonamide F14-(2-Methoxyphenyl)-N-(3-(methylsulfonyl)phenyl) a n.t. n.t. n.t. n.t.n.t. pyridin-2-amine G1[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino) a c c c d dphenyl]methanesulfonamide G2[3-((4-(2-Methoxyphenyl)pyridin-2-yl)amino)phenyl] a n.t. b n.t. n.t. dmethanesulfonamide G3 1-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2- an.t. c n.t. n.t. d yl)amino)phenyl]-N,N-dimethylmethanesulfonamide H12-[3-((4-(2-Methoxyphenyl)pyridin-2-yl)amino)phenyl] a n.t. c n.t. n.t.d ethanesulfonamide J1 N-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2- an.t. b n.t. n.t. d yl)amino)phenyl]methanesulfonamide J2N-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2- a n.t. b n.t. n.t. dyl)amino)phenyl]acetamide K11-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2- b n.t. c n.t. n.t. dyl)amino)phenyl]-N-propylmethanesulfonamide Activity range “a” means,that the compounds do have a IC₅₀ (inhibitory concentration at 50% ofmaximal effect) <100 nM, activity range “b” means, that the compounds dohave a IC₅₀ between 100 and 1000 nM, activity range “c” means that thecompounds do have an IC₅₀ between 1000 and 10000 nM, activity range “d”means that the compounds do have an IC₅₀ > 10000 nM; “n.t.” means thatthe compounds have not been tested in this assay. {circle around (1)}:Compound Number {circle around (2)}: CDK9 LANCE assay (activity range){circle around (3)}: CDK1 LANCE assay (activity range) {circle around(4)}: CDK2 LANCE assay (activity range) {circle around (5)}: CDK4 LANCEassay (activity range) {circle around (6)}: CDK6 LANCE assay (activityrange) {circle around (7)}: CDK7 LANCE assay (activity range)3. Cellular Assays

The cellular activity of the compounds according to the presentinvention are shown in Table 6 as half-maximal inhibition constant(IC₅₀) values on LPS-induced TNF alpha release in PBMCs, NF-kappaBreporter gene activation, cellular CDK9 activity (RNA Polymerase II Ser2phosphorylation), and cell viability in Hela- or MDAMB468-Cells,respectively.

TABLE 6 Inhibition of LPS-induced TNF alpha release in PBMCs, NF-kappaBreporter gene activation, cellular CDK9 activity (RNA Polymerase II Ser2phosphorylation), and cell viability in Hela- or MDAMB468-Cells bycompounds according to the present invention. {circle around (1)}Nomenclature {circle around (2)} {circle around (3)} {circle around (4)}{circle around (5)} {circle around (6)} B14-(2-Methoxyphenyl)-N-phenylpyridin-2-amine d d n.t. n.t. d Cl4-(2-Methoxyphenyl)-N-(3-nitrophenyl)pyridin-2-amine c c n.t. n.t. d D13-[(4-(2-Methoxyphenyl)pyridin-2-yl)amino]benzenesulfonamide b b c b bE1 4-[(4-(2-Methoxyphenyl)pyridin-2-yl)amino]benzenesulfonamide c c n.t.d c F1 4-(2-Methoxyphenyl)-N-(3-(methylsulfonyl)phenyl)pyridin-2-amine cc n.t. c c G1[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl] b b n.t. c cmethanesulfonamide G31-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]- n.t. n.t.n.t. d c N,N-dimethylmethanesulfonamide J1N-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl] n.t. n.t.n.t. c c methanesulfonamide J2N-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl] n.t. n.t.n.t. d c acetamide K11-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]-N- n.t.n.t. n.t. d d propylmethanesulfonamide Activity range “a” means, thatthe compounds do have a IC₅₀ < 100 nM, activity range “b” means, thatthe compounds do have a IC₅₀ between 100 and 1000 nM, activity range “c”means that the compounds do have an IC₅₀ between 1000 and 10000 nM,activity range “d” means that the compounds do have an IC₅₀ > 10000 nM;“n.t.” means that the compounds have not been tested in this assay.{circle around (1)}: Compound Number {circle around (2)}: TNF alpharelease (activity range) {circle around (3)}: NF-kappaB activation(activity range) {circle around (4)}: RNA Polymerase II Ser2Phosphorylation (activity range) {circle around (5)}: Cell Viability -Hela cells (activity range) {circle around (6)}: Cell Viability -MDAMB468 cells (activity range)

The invention claimed is:
 1. Compounds having the general formula (III)

wherein L is a bond or —CR⁵R⁶—, —CR⁵R⁶—CR⁷R⁸—, —CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰—,—CR⁵R⁶—CR⁷R⁸—CR⁹R¹⁰—CR¹¹R¹²—; R⁵—R¹² represent independently of eachother —H, —CH₃, —C₂H₅, —C₃H₇, —F, —Cl, —Br, —I; R³ is selected from —H,—NO₂, —NH₂, —CN, —F, —Cl, —Br, —I, —CH₃, —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —O—CH₃, —O—C₂H₅, —O—C₃H₇,—O—CH(CH₃)₂, —O—C₄H₉, —O—CH₂—CH(CH₃)₂, —O—CH(CH₃)—C₂H₅, —O—C(CH₃)₃,—CR¹³R¹⁴R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶R²¹, —O—CR¹³R¹⁴R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰R²¹,—O—CR¹³R¹⁴—CR¹⁵R¹⁶R²¹, —O—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸R²¹, —SO₂R²²,—CONR²³R²⁴, —NR²⁵COR²², —O—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰R²¹,—NR²⁵SO₂NR²³R²⁴, —NR²⁵SO₂R²², —NR²⁵CONR²³R²⁴, —SO₂NR²³R²⁴, —SO(NR²⁶)R²²,—NR²³R²⁴; R¹³—R²¹ and R²⁹—R³² represent independently of each other —H,—CH₃, —C₂H₅, —C₃H₇, —C₄H₉, —F, —Cl, —Br, —I; R²⁶ is —H, —CH₃, —C₂H₅,—C₃H₇, —CH(CH₃)₂, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,—CH(CH₃)—C₃H₇, —CH₂—CH(CH₃)—C₂H₅, —CH(CH₃)—CH(CH₃)₂, —C(CH₃)₂—C₂H₅,—CH₂—C(CH₃)₃, —CH(C₂H₅)₂, —C₂H₄—CH(CH₃)₂, —C₆H₁₃, —C₃H₆—CH(CH₃)₂,—C₂H₄—CH(CH₃)—C₂H₅, —CH(CH₃)—C₄H₉, —CH₂—CH(CH₃)—C₃H₇,—CH(CH₃)—CH₂—CH(CH₃)₂, —CH(CH₃)—CH(CH₃)—C₂H₅, —CH₂—CH(CH₃)—CH(CH₃)₂,—CH₂—C(CH₃)₂—C₂H₅, —C(CH₃)₂—C₃H₇, —C(CH₃)₂—CH(CH₃)₂, —C₂H₄—C(CH₃)₃,—CH(CH₃)—C(CH₃)₃, —CR¹³R¹⁴R²¹, —COR²⁸, —CR¹³R¹⁴—CR¹⁵R¹⁶R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁸—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰—CR³¹R³²R²¹, —COOR²⁸, —R²⁷; R²²,and R²⁸ are independently selected from —R^(27′), —CR¹³R¹⁴R²¹, —CH₃,—C₂H₅, —CR¹³R¹⁴—CR¹⁵R¹⁶R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰—CR³¹R³²R²¹, —C₃H₇, —CH₂Ph;—CH₂Ph the phenyl group of which may further be substituted by one, two,three, four or five substituents selected from the group consisting of—CH₃, —C₂H₅, —C₃H₇, —F, —Cl, —Br and —I; R²⁷, R^(27′) and R^(27″) areindependently selected from

these C₃-C₁₀-cycloalkyl groups may further be substituted by one, two,three, four, five or more substituents selected from the groupconsisting of —F, —Cl, —Br and —I; R²³, R²⁴, R⁷⁷ and R⁷⁸ areindependently of each other selected from —H, —CH₃, —C₂H₅, —CR¹³R¹⁴R²¹,—C₃H₇, —CR¹³R¹⁴—CR¹⁵R¹⁶R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸R²¹, —CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰—CR³¹R³²R²¹,—CR¹³R¹⁴—CR¹⁵R¹⁶—O—R³³, —CR¹³R¹⁴—CR¹⁵R¹⁶—NR³³R³⁴,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—NR³³R³⁴,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—NR³³R³⁴,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—O—R³³,—CR¹³R¹⁴—CR¹⁵R¹⁶—CR¹⁷R¹⁸—CR¹⁹R²⁰—CR²⁹R³⁰—NR³³R³⁴, -Ph, —CH₂PH, phenylgroup which may further be substituted by one, two, three, four or fivesubstituents selected from the group consisting of —CH₃, —C₂H₅, —C₃H₇,—F, —Cl, —Br and —I; —CH₂Ph the phenyl group of which may further besubstituted by one, two, three, four or five substituents selected fromthe group consisting of —CH₃, —C₂H₅, —C₃H₇, —F, —Cl, —Br and —I; or bothresidues R²³ and R²⁴ together form with the nitrogen atom to which theyare attached a azetidine, pyrrolidine, piperidine, piperazine, azepane,or morpholine ring; R³³ and R³⁴ represent independently of each other—H, —CH₃, —C₂H₅, —C₃H₇, —C₄H₉, —CH₂Ph, —COOC(CH₃)₃, —COOCH₃, —COOCH₂CH₃,—COOCH₂CH₂CH₃, —COOCH(CH₃)₂, —COOCH₂Ph, —COCH₃; and R²⁵ is selected from—H, —CH₃, —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅or —C(CH₃)₃; R⁴ is selected from —H, —NO₂, —CN, —F, —Cl, —Br, —I,—CR³⁵R³⁶R³⁷, —CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³R³⁷, —O—CR³⁵R³⁶—CR³⁸R³⁹R³⁷,—O—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹R³⁷, —CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹R³⁷,—O—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³R³⁷, —CR³⁵R³⁶—CR³⁸R³⁹R³⁷,—O—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³—CR⁴⁴R⁴⁵R³⁷, —O—CR³⁵R³⁶R³⁷,—O—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³—CR⁴⁴R⁴⁵—CR⁴⁶R⁴⁷R³⁷,—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³—CR⁴⁴R⁴⁵R³⁷,—CR³⁵R³⁶—CR³⁸R³⁹—CR⁴⁰R⁴¹—CR⁴²R⁴³—CR⁴⁴R⁴⁵—CR⁴⁶R⁴⁷R³⁷, —OCH₂Ph, —R^(27″),—O—R^(27″); R³⁵—R⁴⁷ and R⁶²—R⁷⁴ represent independently of each other—H, —CR⁴⁸R⁴⁹R⁵⁰, —CR⁴⁸R⁴⁹—CR⁵¹R⁵²R⁵⁰, —CR⁴⁸R⁴⁹—CR⁵¹R⁵²—CR⁵³R⁵⁴R⁵⁰,—CR⁴⁸R⁴⁹—CR⁵¹R⁵²—CR⁵³R⁵⁴—CR⁵⁵R⁵⁶R⁵⁰, —F, —Cl, —Br, —I; R⁴⁸—R⁵⁶ representindependently of each other —H, —F, —Cl, —Br, —I; R⁴ together with R²²or R²³ or R²⁴ or R²⁵ may form a group —CH₂CH₂— or —CH₂CH₂CH₂— if R⁴ isattached ortho to -L-R³; R² is

R⁵⁷ is selected from —H, —OH, —NO₂, —CN, —F, —Cl, —Br, —I, —NR⁶⁰R⁶¹,-D-R⁶⁴, -D-NR⁶⁰R⁶¹, —O-D-R⁶⁴, —CHO, —CH₂OH, —CO—R⁶⁰, —CH₂OR⁶⁰; D, D′ andD″ represent independently of each other —CR⁶²R⁶³—, —CR⁶²R⁶³—CR⁶⁵R⁶⁶—,—CR⁶²R⁶³—CR⁶⁵R⁶⁶—CR⁶⁷R⁶⁸—, —CR⁶²R⁶³—CR⁶⁵R⁶⁶—CR⁶⁷R⁶⁸—CR⁶⁹R⁷⁰—; R⁶⁰, R⁶¹,R⁷⁵ and R⁷⁶ represent independently of each other —H, —CH₃, —C₂H₅,—C₃H₇, —CH(CH₃)₂, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃,-(cyclo-C₃H₅); x is 0, 1, 2 or 3; B is —OCH₃, —OC₂H₅, —OC₃H₇,—O-cyclo-C₃H₅, —OCH(CH₃)₂, —OC(CH₃)₃, —OC₄H₉;

and enantiomers, stereoisomeric forms, mixtures of enantiomers,diastereomers, mixtures of diastereomers, acid salt forms, tautomers,and racemates of the above mentioned compounds and pharmaceuticallyacceptable salts thereof.
 2. Compounds according to claim 1, wherein thesubstituent-L-R³ represents —NO₂, —NH₂, —SO₂R²², —CONR²³R²⁴, —NR²⁵COR²²,—NR²⁵SO₂NR²³R²⁴, —NR²⁵SO₂R²², —NR²⁵CONR²³R²⁴, —SO₂NR²³R²⁴, —SO(NR²⁶)R²²,—NR²³R²⁴, —CH₂—NO₂, —CH₂—NH₂, —CH₂—SO₂R²², —CH₂—CONR²³R²⁴,—CH₂—NR²⁵COR²², —CH₂—NR²⁵SO₂NR²³R²⁴, —CH₂—NR²⁵SO₂R²²,—CH₂—NR²⁵CONR²³R²⁴, —CH₂—SO₂NR²³R²⁴, —CH₂—SO(NR²⁶)R²², —CH₂—NR²³R²⁴,—CH₂CH₂—NO₂, —CH₂CH₂—NH₂, —CH₂CH₂—SO₂R²², —CH₂CH₂—CONR²³R²⁴,—CH₂CH₂—NR²⁵COR²², —CH₂CH₂—NR²⁵SO₂NR²³R²⁴, —CH₂CH₂—NR²⁵SO₂R²²,—CH₂CH₂—NR²⁵CONR²³R²⁴, —CH₂CH₂—SO₂NR²³R²⁴, —CH₂CH₂—SO(NR²⁶)R²², or—CH₂CH₂—NR²³R²⁴.
 3. Compounds according to claim 1 wherein -L-R³represents —NO₂, —NH₂, —NH(CH₃), —NH(C₂H₅), —NH(C₃H₇), —N(CH₃)₂,—N(C₂H₅)₂, —N(C₃H₇)₂, —SO₂CH₃, —SO₂C₂H₅, —SO₂C₃H₇, —CONH₂, —CONH(CH₃),—CONH(C₂H₅), —CONH(C₃H₇), —CON(CH₃)₂, —CON(C₂H₅)₂, —CON(C₃H₇)₂,—NHCOCH₃, —NHCOC₂H₅, —NHCOC₃H₇, —NHSO₂NH₂, —NHSO₂NH(CH₃),—NHSO₂NH(C₂H₅), —NHSO₂NH(C₃H₇), —NHSO₂N(CH₃)₂, —NHSO₂N(C₂H₅)₂,—NHSO₂N(C₃H₇)₂, —NHSO₂CH₃, —NHSO₂C₂H₅, —NHSO₂C₃H₇, —NHCONH₂,—NHCONH(CH₃), —NHCONH(C₂H₅), —NHCONH(C₃H₇), —NHCON(CH₃)₂, —NHCON(C₂H₅)₂,—NHCON(C₃H₇)₂, —SO₂NH₂, —SO₂NH(CH₃), —SO₂NH(C₂H₅), —SO₂NH(C₃H₇),—SO₂N(CH₃)₂, —SO₂N(C₂H₅)₂, —SO₂N(C₃H₇)₂, —SO(NH)CH₃, —SO(NH)C₂H₅,—SO(NH)C₃H₇, —CH₂—NO₂, —CH₂—NH₂, —CH₂—NH(CH₃), —CH₂—NH(C₂H₅),—CH₂—NH(C₃H₇), —CH₂—N(CH₃)₂, —CH₂—N(C₂H₅)₂, —CH₂—N(C₃H₇)₂, —CH₂—SO₂CH₃,—CH₂—SO₂C₂H₅, —CH₂—SO₂C₃H₇, —CH₂—CONH₂, —CH₂—CONH(CH₃), —CH₂—CONH(C₂H₅),—CH₂—CONH(C₃H₇), —CH₂—CON(CH₃)₂, —CH₂—CON(C₂H₅)₂, —CH₂—CON(C₃H₇)₂,—CH₂—NHCOCH₃, —CH₂—NHCOC₂H₅, —CH₂—NHCOC₃H₇, —CH₂—NHSO₂NH₂,—CH₂—NHSO₂NH(CH₃), —CH₂—NHSO₂NH(C₂H₅), —CH₂—NHSO₂NH(C₃H₇),—CH₂—NHSO₂N(CH₃)₂, —CH₂—NHSO₂N(C₂H₅)₂, —CH₂—NHSO₂N(C₃H₇)₂,—CH₂—NHSO₂CH₃, —CH₂—NHSO₂C₂H₅, —CH₂—NHSO₂C₃H₇, —CH₂—NHCONH₂,—CH₂—NHCONH(CH₃), —CH₂—NHCONH(C₂H₅), —CH₂—NHCONH(C₃H₇),—CH₂—NHCON(CH₃)₂, —CH₂—NHCON(C₂H₅)₂, —CH₂—NHCON(C₃H₇)₂, —CH₂—SO₂NH₂,—CH₂—SO₂NH(CH₃), —CH₂—SO₂NH(C₂H₅), —CH₂—SO₂NH(C₃H₇), —CH₂—SO₂N(CH₃)₂,—CH₂—SO₂N(C₂H₅)₂, —CH₂—SO₂N(C₃H₇)₂, —CH₂—SO(NH)CH₃, —CH₂—SO(NH)C₂H₅,—CH₂—SO(NH)C₃H₇, —CH₂CH₂—NO₂, —CH₂CH₂—NH₂, —CH₂—CH₂—NH(CH₃),—CH₂—CH₂—NH(C₂H₅), —CH₂—CH₂—NH(C₃H₇), —CH₂—CH₂—N(CH₃)₂,—CH₂—CH₂—N(C₂H₅)₂, —CH₂—CH₂—N(C₃H₇)₂, —CH₂—CH₂—SO₂CH₃, —CH₂—CH₂—SO₂C₂H₅,—CH₂—CH₂—SO₂C₃H₇, —CH₂—CH₂—CONH₂, —CH₂—CH₂—CONH(CH₃),—CH₂—CH₂—CONH(C₂H₅), —CH₂—CH₂—CONH(C₃H₇), —CH₂—CH₂—CON(CH₃)₂,—CH₂—CH₂—CON(C₂H₅)₂, —CH₂—CH₂—CON(C₃H₇)₂, —CH₂—CH₂—NHCOCH₃,—CH₂—CH₂—NHCOC₂H₅, —CH₂—CH₂—NHCOC₃H₇, —CH₂—CH₂—NHSO₂N H₂,—CH₂—CH₂—NHSO₂NH(CH₃), —CH₂—CH₂—NHSO₂NH(C₂H₅), —CH₂—CH₂—NHSO₂NH(C₃H₇),—CH₂—CH₂—NHSO₂N(CH₃)₂, —CH₂—CH₂—NHSO₂N(C₂H₅)₂, —CH₂—CH₂—NHSO₂N(C₃H₇)₂,—CH₂—CH₂—NHSO₂CH₃, —CH₂—CH₂—NHSO₂C₂H₅, —CH₂—CH₂—NHSO₂C₃H₇,—CH₂—CH₂—NHCONH₂, —CH₂—CH₂—NHCONH(CH₃), —CH₂—CH₂—NHCONH(C₂H₅),—CH₂—CH₂—NHCONH(C₃H₇), —CH₂—CH₂—NHCON(CH₃)₂, —CH₂—CH₂—NHCON(C₂H₅)₂,—CH₂—CH₂—NHCON(C₃H₇)₂, —CH₂—CH₂—SO₂N H₂, —CH₂—CH₂—SO₂NH(CH₃),—CH₂—CH₂—SO₂NH(C₂H₅), —CH₂—CH₂—SO₂NH(C₃H₇), —CH₂—CH₂—SO₂N (CH₃)₂,—CH₂—CH₂—SO₂N (C₂H₅)₂, —CH₂—CH₂—SO₂N(C₃H₇)₂, —CH₂—CH₂—SO(NH)CH₃,—CH₂—CH₂—SO(NH)C₂H₅, —CH₂—CH₂—SO(NH)C₃H₇, and R² has the meanings asdefined in claim
 1. 4. Compounds according to claim 1, wherein thesubstituent-L-R³ represents —NO₂, —NH₂, —SO₂NH₂, —SO₂—NH—C(CH₃)₃,—SO₂CH₃, —CH₂—SO₂N H₂, —CH₂—SO₂—N(CH₃)₂, —CH₂—CH₂—SO₂N H₂, —NHSO₂CH₃,—NHCOCH₃, or —CH₂—SO₂—NH(CH₂CH₂CH₃).
 5. A compound selected from thegroup consisting of: 4-(2-Methoxyphenyl)-N-phenylpyridin-2-amine,4-(2-Methoxyphenyl)-N-(3-nitrophenyl)pyridin-2-amine,4-(4-Fluoro-2-methoxyphenyl)-N-(3-nitrophenyl)pyridin-2-amine,3-[(4-(2-Methoxyphenyl)pyridin-2-yl)amino]benzenesulfonamide,4-(2-Methoxyphenyl)-N-(3-(methylsulfonyl)phenyl)pyridin-2-amine,[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]methanesulfonamide,[3-((4-(2-Methoxyphenyl)pyridin-2-yl)amino)phenyl]methanesulfonamide,2-[3-((4-(2-Methoxyphenyl)pyridin-2-yl)amino)phenyl]ethanesulfonamide,N-(tert-Butyl)-3-[(4-(2-methoxyphenyl)pyridin-2-yl)amino]benzenesulfonamide,1-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]-N,N-dimethyl-methanesulfonamide,N1-(4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)benzene-1,3-diamine,N-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]methane-sulfonamide,andN-[3-((4-(4-Fluoro-2-methoxyphenyl)pyridin-2-yl)amino)phenyl]acetamide.6. Pharmaceutical composition comprising at least one compound accordingto claim 1 as an active ingredient, together with at least onepharmaceutically acceptable carrier, excipient and/or diluent. 7.Pharmaceutical composition according to claim 6 further comprising oneor more further anti-tumor agents.